Compositions, formulations, and methods for hair treatment

ABSTRACT

Compositions and formulations for hair treatment are provided herein. Methods for hair treatment, such as methods for preventing or treating hair loss or hair thinning, are also provided herein. The methods may promote hair growth, hair restoration or hair thickening, or increase hair density or hair growth rate.

CROSS REFERENCE

This application is a continuation of International Patent Application No. PCT/US22/39800, filed Aug. 9, 2022, which claims the benefit of U.S. Provisional Patent Application No. 63/231,533, filed Aug. 10, 2021, each of which is incorporated by reference herein in its entirety.

SUMMARY

Hair loss or thinning is a common problem which is, for example, naturally occurring or chemically promoted through the long-term use of certain chemicals (e.g., commercial products or therapeutic drugs). Often such hair loss or thinning is accompanied by lack of hair re-growth which causes partial or full baldness. While hair loss is often thought of as a man's problem, at least a third of women will experience thinning hair at some point in their lives.

The disclosure provides a method for preventing or treating hair loss or hair thinning (whether or not a diagnosis of hair loss or hair thinning has been made), the method comprising administering to a subject in need thereof a composition comprising a compound having a structure of a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII_(A)), (VII_(B)), or (VIII).

In certain aspects, disclosed herein is a method for preventing or treating hair loss or hair thinning (whether or not a diagnosis of hair loss or hair thinning has been made), the method comprising administering to a subject in need thereof a composition comprising a compound having a structure of Formula (VII_(B)):

or a salt thereof, wherein:

-   -   B is aryl or heteroaryl, wherein the heteroaryl is selected from         pyridine, pyrimidine, oxazole, furan, pyran, thiophene,         isoxazole, benzimidazole, benzthiazole, and imidazopyridine;     -   R¹ is selected from hydrogen, C₁₋₆ alkyl or C₁₋₆ haloalkyl,         —S-alkyl, —S-haloalkyl, —S(O)(O)R^(a); wherein R^(a) is selected         from the group consisting of hydrogen, C₁₋₆ alkyl, or C₁₋₆         haloalkyl;     -   R² is selected from —OH, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —SR^(b),         —NH₂, alkylamino, and imino, wherein R² is selected from the         group consisting of hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and

and

-   -   R³ and R⁴ is independently selected from the group consisting of         hydrogen, C₁₋₆ alkyl or C₁₋₆ haloalkyl.

In some embodiments, B is heteroaryl. In some embodiments, the heteroaryl is furan. In some embodiments, R¹ is hydrogen or S(O)(O)R^(a). In some embodiments, R^(a) is methyl or ethyl. In some embodiments, R² is imino or —SR^(b). In some embodiments, R^(b) is methyl or

In some embodiments, R³ is hydrogen or ethyl. In some embodiments, R⁴ is hydrogen.

In some embodiments, the compound of Formula (VII_(B)) or the salt thereof is selected from:

In certain aspects, disclosed herein is a method for preventing or treating hair loss or hair thinning (whether or not a diagnosis of hair loss or hair thinning has been made), the method comprising administering to a subject in need thereof a composition comprising a compound having a structure of Formula (VII_(A)):

or a salt thereof, wherein:

-   -   A is aryl or heteroaryl, wherein the heteroaryl is selected from         pyridine, pyrimidine, oxazole, furan, pyran, thiophene,         isoxazole, benzimidazole, benzthiazole, and imidazopyridine;     -   R¹ is C₁₋₆ alkyl or C₁₋₆ haloalkyl; and     -   R² is —C(O)OH, —C(O)O-alkyl, or —C(O)O-haloalkyl.

In some embodiments, A is aryl. In some embodiments, the aryl is phenyl. In some embodiments, R¹ is C₁₋₆ alkyl. In some embodiments, R² is —C(O)O-alkyl.

In some embodiments, the compound of Formula (VII_(A)) is

or a salt thereof.

In certain aspects, disclosed herein is a method for preventing or treating hair loss or hair thinning (whether or not a diagnosis of hair loss or hair thinning has been made), the method comprising administering to a subject in need thereof a composition comprising a compound having a structure of Formula (VIII):

or a salt thereof, wherein:

-   -   m is 0, 1, or 2; and     -   R^(x) is each independently C₁₋₆ alkyl, C₅₋₈ aryl, C₁₋₆         haloalkyl, alkylaryl, or haloalkylaryl.

In some embodiments, m is 2. In some embodiments, R^(x) is each independently methyl or phenyl.

In some embodiments, the compound of Formula (VIII) is

or a salt thereof.

In certain aspects, disclosed herein is a method for treating hair loss or hair thinning (whether or not a diagnosis of hair loss or hair thinning has been made), the method comprising administering to a subject in need thereof a composition comprising a compound having a structure of Formula (VII_(B)):

or a salt thereof, wherein:

-   -   B is aryl or heteroaryl;     -   R¹ is selected from hydrogen, C₁₋₆ alkyl or C₁₋₆ haloalkyl,         —S-alkyl, —S-haloalkyl, —S(O)(O)R^(a); wherein R^(a) is selected         from the group consisting of hydrogen, C₁₋₆ alkyl, or C₁₋₆         haloalkyl;     -   R² is selected from —OH, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —SR,         —NH₂, alkylamino, and imino, wherein R² is selected from the         group consisting of hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and

and

R³ and R⁴ is independently selected from the group consisting of hydrogen, C₁₋₆ alkyl or C₁₋₆ haloalkyl.

In some embodiments, B is heteroaryl. In some embodiments, the heteroaryl is furan. In some embodiments, R¹ is hydrogen or S(O)(O)R^(a). In some embodiments, R^(a) is methyl or ethyl. In some embodiments, R² is imino or —SR^(b). In some embodiments, R^(b) is methyl or

In some embodiments, R³ is hydrogen or ethyl. In some embodiments, R⁴ is hydrogen. In some embodiments, the compound of Formula (VII_(B)) or the salt thereof is selected from:

In certain aspects, disclosed herein is a method for treating hair loss or hair thinning (whether or not a diagnosis of hair loss or hair thinning has been made), the method comprising administering to a subject in need thereof a composition comprising a compound having a structure of Formula (VII_(A)):

or a salt thereof, wherein:

-   -   A is aryl or heteroaryl, wherein the heteroaryl is selected from         pyridine, pyrimidine, oxazole, furan, pyran, thiophene,         isoxazole, benzimidazole, benzthiazole, and imidazopyridine;     -   R¹ is C₁₋₆ alkyl or C₁₋₆ haloalkyl; and     -   R² is —C(O)OH, —C(O)O-alkyl, or —C(O)O-haloalkyl.

In some embodiments, A is aryl. In some embodiments, the aryl is phenyl. In some embodiments, R¹ is C₁₋₆ alkyl. In some embodiments, R² is —C(O)O-alkyl.

In some embodiments, the compound of Formula (VII_(A)) is

or a salt thereof.

In certain aspects, disclosed herein is a method for treating hair loss or hair thinning (whether or not a diagnosis of hair loss or hair thinning has been made), the method comprising administering to a subject in need thereof a composition comprising a compound having a structure of Formula (VIII):

or a salt thereof, wherein:

-   -   m is 0, 1, or 2; and     -   R^(x) is each independently C₁₋₆ alkyl, C₅₋₈ aryl, C₁₋₆         haloalkyl, alkylaryl, or haloalkylaryl.

In some embodiments, m is 2. In some embodiments, R^(x) is each independently methyl or phenyl.

In some embodiments, the compound of Formula (VIII) is

or a salt thereof.

In certain aspects, disclosed herein is a method for preventing or treating hair loss or hair thinning (whether or not a diagnosis of hair loss or hair thinning has been made), the method comprising administering to a subject in need thereof a composition comprising a compound having a structure of Formula (I):

or a salt thereof, wherein:

Y¹ is O or S;

Y² is O or S;

Y³ is O or S;

R¹ is selected from H, alkyl, haloalkyl, alkenyl, haloalkenyl, aryl (e.g., phenyl), and aralkyl (e.g., benzyl), wherein the aryl or aralkyl is optionally substituted with one or more substituents independently selected from halogen, alkyl, alkoxy, and haloalkoxy;

R² is selected from H, alkyl, alkenyl, haloalkyl, and haloalkenyl;

A is aryl (e.g., phenyl) or heteroaryl (e.g., pyrimidinyl);

p is 0, 1, 2, or 3; and

R^(x) is each independently selected from halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, —OH, alkoxy, haloalkoxy, —O-alkylene-C(O)OH, nitro, —NH₂, alkylamino, dialkylamino, and haloalkylamino; or, alternatively, two R^(x) together with the atoms to which they are attached to form (e.g., C₄-C₆) cycloalkyl or (e.g., 5- or 6-membered) heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more substituents independently selected from halogen, alkyl, and haloalkyl.

In some embodiments, R² is selected from (e.g., C₁₋₆, such as C₁₋₄) alkyl, (e.g., C₁₋₆, such as C₁₋₄) alkenyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkyl, and (e.g., C₁₋₆, such as C₁₋₄) haloalkenyl. In some embodiments, Y¹ is S. In some embodiments, Y³ is S. In some embodiments, A is

wherein Q¹ and Q² are each independently CH or N. In some embodiments, A is

In some embodiments, the compound of Formula (I) has a structure of Formula (I_(A1)) or (I_(A2)):

wherein: R^(x1), R^(x2), R^(x3), R^(x1), R^(x2), and R^(x3) are each independently selected from halogen, (e.g., C₁₋₆, such as C₁₋₄) alkyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkyl, (e.g., C₁₋₆, such as C₁₋₄) alkenyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkenyl, —OH, (e.g., C₁₋₆, such as C₁₋₄) alkoxy, (e.g., C₁₋₆, such as C₁₋₄) haloalkoxy, —O-alkylene-C(O)OH, nitro, —NH₂, (e.g., C₁₋₆, such as C₁₋₄) alkylamino, (e.g., C₁₋₆, such as C₁₋₄) dialkylamino, and (e.g., C₁₋₆, such as C₁₋₄) haloalkylamino. In some embodiments, the compound of Formula (I) has a structure of Formula (I_(B1)):

wherein: R^(x4) and R^(x5) are each independently selected from halogen, (e.g., C₁₋₆, such as C₁₋₄) alkyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkyl, (e.g., C₁₋₆, such as C₁₋₄) alkenyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkenyl, —OH, (e.g., C₁₋₆, such as C₁₋₄) alkoxy, (e.g., C₁₋₆, such as C₁₋₄) haloalkoxy, —O-alkylene-C(O)OH, nitro, —NH₂, (e.g., C₁₋₆, such as C₁₋₄) alkylamino, (e.g., C₁₋₆, such as C₁₋₄) dialkylamino, and (e.g., C₁₋₆, such as C₁₋₄) haloalkylamino. In some embodiments, the compound of Formula (I) has a structure of Formula (I_(B2)):

wherein: R^(x6) and R^(x7) are each independently selected from halogen, (e.g., C₁₋₆, such as C₁₋₄) alkyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkyl, (e.g., C₁₋₆, such as C₁₋₄) alkenyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkenyl, —OH, (e.g., C₁₋₆, such as C₁₋₄) alkoxy, (e.g., C₁₋₆, such as C₁₋₄) haloalkoxy, —O-alkylene-C(O)OH, nitro, —NH₂, (e.g., C₁₋₆, such as C₁₋₄) alkylamino, (e.g., C₁₋₆, such as C₁₋₄) dialkylamino, and (e.g., C₁₋₆, such as C₁₋₄) haloalkylamino; or, alternatively, R^(x6) and R^(x7) together with the atoms to which they are attached to form cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more substituents independently selected from halogen, (e.g., C₁₋₆, such as C₁₋₄) alkyl, and (e.g., C₁₋₆, such as C₁₋₄) haloalkyl. In some embodiments, the compound of Formula (I) has a structure of Formula (I_(C1)) or (I_(C2)):

wherein: R^(x8) and R^(x9) are each independently selected from halogen, (e.g., C₁₋₆, such as C₁₋₄) alkyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkyl, (e.g., C₁₋₆, such as C₁₋₄) alkenyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkenyl, —OH, (e.g., C₁₋₆, such as C₁₋₄) alkoxy, (e.g., C₁₋₆, such as C₁₋₄) haloalkoxy, —O-alkylene-C(O)OH, nitro, —NH₂, (e.g., C₁₋₆, such as C₁₋₄) alkylamino, (e.g., C₁₋₆, such as C₁₋₄) dialkylamino, and (e.g., C₁₋₆, such as C₁₋₄) haloalkylamino.

In some embodiments, the compound of Formula (I) or the salt thereof is selected from:

and a salt of any one thereof.

In certain aspects, the disclosure provides a method for preventing or treating hair loss or hair thinning (whether or not a diagnosis of hair loss or hair thinning has been made), the method comprising administering to a subject in need thereof a composition comprising a compound having a structure of Formula (II):

or a salt thereof, wherein:

R^(y) is each independently alkyl or haloalkyl;

m is 0, 1, or 2;

L¹ is selected from bond, —O—, —S—, —N(R^(a1))—, —C(O)—, —C(O)-alkylene-, —C(O)-alkylene-O—, -alkylene-C(O)—, -alkylene-C(O)—O—, —C(O)O—, —OC(O)—, —C(O)N(R^(a2))—, —N(R^(a3))C(O)—, —N(R^(a4))C(O)N(R^(a5))—, —N(R^(a6))C(O)O—, —OC(O)N(R^(a7))—, —S(O)₂—, —OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—, —S(O)₂O—, —N(R^(a8))S(O)₂—, —S(O)₂N(R^(a9))—, —N(R^(a10))S(O)—, —S(O)N(R^(a11))—, —N(R^(a12))S(O)₂N(R^(a13))—, and —N(R^(a14))S(O)N(R^(a15))—; and R¹ is selected from H, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, cycloalkyl, alkylcycloalkyl, halocycloalkyl, aryl (e.g., phenyl), alkylaryl, heteroaryl, —O-aryl, —O-alkylaryl, and —O-heteroaryl.

In some embodiments, the compound of Formula (II) has a structure of Formula (II_(A)):

In some embodiments, R^(y) is C₁-C₆ (e.g., C₁-C₄) alkyl (e.g., methyl). In some embodiments, m is 1. In some embodiments, L¹ is selected from —C(O)—, —C(O)— alkylene-O—, and —S(O)₂—. In some embodiments, R¹ is selected from alkyl, cycloalkyl, aryl, alkylaryl, —O-aryl, and —O-alkylaryl.

In some embodiments, the compound of Formula (II) or the salt thereof is selected from:

and a salt ofany one thereof.

In certain aspects, the disclosure provides a method for preventing or treating hair loss or hair thinning (whether or not a diagnosis of hair loss or hair thinning has been made), the method comprising administering to a subject in need thereof a composition comprising a compound having a structure of Formula (III):

or a salt thereof, wherein:

A is aryl or heteroaryl;

p is 0, 1, or 2;

R^(y) is each independently alkyl or haloalkyl;

q is 0, 1, or 2;

R^(z) is each independently alkyl or haloalkyl; and

R¹ and R² are each independently selected from H, optionally substituted aryl, —NH—C(O)—NH— cycloalkyl (e.g., adamantyl), —C(O)—NH-cycloalkyl, and —NH—C(O)-cycloalkyl; or,

alternatively, R¹ and R² join together with the nitrogen atom to which they are attached to form N-heterocyclyl (e.g., piperazinyl) or —N═R^(c), wherein R^(c) is an optionally substituted aryl or optionally substituted heteroaryl.

In some embodiments, R¹ and R² join together with the nitrogen atom to which they are attached to form

wherein R^(x) is selected from alkyl, haloalkyl, -alkylene-OH, -alkylene-O-alkyl, -alkylene-aryl, and -alkylene-arylene-alkyl. In some embodiments, R¹ and R² join together with the nitrogen atom to which they are attached to form

In some embodiments, R¹ and R² join together with the nitrogen atom to which they are attached to form an optionally substituted piperazinyl. In some embodiments, A is pyridinyl

In some embodiments, the compound of Formula (III) or the salt thereof is selected from:

and a salt of any one thereof.

In certain aspects, the disclosure provides a method for preventing or treating hair loss or hair thinning (whether or not a diagnosis of hair loss or hair thinning has been made), the method comprising administering to a subject in need thereof a composition comprising a compound having a structure of Formula (IV):

or a salt thereof, wherein:

A is heteroaryl;

q is 0, 1, 2, or 3; and

R^(x) is selected from alkyl, haloalkyl, alkoxyl, haloalkoxyl, —SH, alkylthio, aryl, and alkoxylaryl.

In some embodiments, the compound of Formula (IV) or the salt thereof is selected from:

and a salt of any one thereof.

In certain aspects, the disclosure provides a method for preventing or treating hair loss or hair thinning (whether or not a diagnosis of hair loss or hair thinning has been made), the method comprising administering to a subject in need thereof a composition comprising a compound having a structure of Formula (V):

or a salt thereof, wherein:

R¹ is H or optionally substituted aryl;

R^(m) and R^(n) join together with the nitrogen atom to which they are attached to form N-heterocyclyl, wherein the N-heterocyclyl is optionally substituted with one or more substituents selected from alkyl, —S(O)H, —S(O)₂H, —S(O)-alkyl, and —S(O)₂-alkyl;

Q¹ is NR^(a1), CR^(b1)R^(b2) or S;

Q³ is N or CR^(b3); and

Q² is NR^(a2) or CR^(b4)R^(b5); wherein:

R^(a1), R^(a2), R^(b1), R^(b2), R^(b3), R^(b4), and R^(b5) are each independently selected from H, optionally substituted aryl, optionally substituted alkylaryl, and optionally substituted arylalkyl.

In some embodiments, Q¹ is CR^(b1)R^(b2) or S. In some embodiments, Q³ is CR^(b3).

In some embodiments, the compound of Formula (V) or the salt thereof is selected from:

and N, and a salt of any one thereof.

In certain aspects, the disclosure provides a method for preventing or treating hair loss or hair thinning (whether or not a diagnosis of hair loss or hair thinning has been made), the method comprising administering to a subject in need thereof a composition comprising a compound having a structure of Formula (VI):

or a salt thereof, wherein:

L⁰ is selected from —C(O)—, —O—, —S—, —C(O)O—, —OC(O)—, —S(O)—, —S(O)₂—, —NH—, and

wherein L¹ is selected from —C(O)—, —O—, —S—, —C(O)O—, —OC(O)—, —S(O)—, —S(O)₂—, and —NH—;

p, q, and m are each independently 0, 1, or 2;

R^(x), R^(y), and R^(z) are each independently selected from alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, —OH, —C(O)OH, or -alkylene-C(O)OH;

A is aryl or heteroaryl;

L² is alkylene, —C(O)—, —O—, —S—, —C(O)O—, —OC(O)—, —S(O)—, —S(O)₂—, —N(H)S(O)₂—, —S(O)₂N(H)—, -alkylene-N(H)S(O)₂—, —S(O)₂N(H)-alkylene-, —NH—, —N═, and —CH═N—N═; and

B is an optionally substituted aryl or optionally substituted heteroaryl.

In some embodiments, L⁰ is

In some embodiments, A is phenyl or piperazinyl. In some embodiments, B is selected from

In some embodiments, L² is selected from alkylene, —S(O)₂N(H)-alkylene-, and —CH═N—N═. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, q is 0. In some embodiments, m is 0. In some embodiments, m is 2. In some embodiments, R^(x) is each independently cyano, alkyl, alkoxy, and nitro. In some embodiments, R^(z) is each independently —OH, —C(O)OH, or -alkylene-C(O)OH.

In some embodiments, the compound of Formula (VI) or the salt thereof is selected from:

and a salt of any one thereof.

In certain aspects, the disclosure provides a method for preventing or treating hair loss or hair thinning (whether or not a diagnosis of hair loss or hair thinning has been made), the method comprising administering to a subject in need thereof a composition comprising a compound selected from:

and a salt of any one thereof.

In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the method comprises at least one additive selected from the group consisting of pharmaceutically acceptable carriers, excipients, adjuvants, and diluents. In some embodiments, the composition is a cosmetic composition. In some embodiments, the method further comprises at least one additive selected from the group consisting of cosmetically acceptable carriers, excipients, adjuvants, and diluents. In some embodiments, the cosmetic composition is formulated as toner, emulsion, cream, gel, shampoo, soap, serum, spray, or oil. In some embodiments, the hair loss is selected from androgenic alopecia, alopecia areata, androgenetic alopecia, gynecologic alopecia, postpartum alopecia, seborrheic alopecia, non-rigid alopecia, senile alopecia, chemotherapy-induced alopecia, radiation-induced alopecia, male-pattern baldness, female-pattern baldness, cicatricial alopecia, alopecia areata telogen effluvium, traction alopecia, and anagen effluvium. In some embodiments, the method promotes hair strength, hair growth, hair restoration or hair thickening of said subject. In some embodiments, the subject has not been diagnosed. In some embodiments, the method increases hair density or hair growth rate of said subject. In some embodiments, the hair is scalp hair, eyelash hair, eyebrow hair, or facial hair.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also “Figure” and “FIG.” herein), of which:

FIG. 1 depicts an exemplary depiction of the dose response curves from compound VII-3, in accordance with one or more embodiments of the present disclosure.

FIG. 2A shows schematic representation of model system, in accordance with one or more embodiments of the present disclosure. Caco-2 cells were cultured on transwells and cultured until a monolayer formed, mimicking the intestinal cell barrier. The cultures were treated with an exemplary compound (VII-3) or vehicle control (0.1% v/v DMSO) on the apical side for 24 hr and cultured in media containing a fluorescent dye (Lucifer yellow, labeled “F”).

FIG. 2B shows apparent permeability of a Caco-2 monolayer dosed with DMSO and an exemplary compound (VII-3), in accordance with one or more embodiments of the present disclosure. No difference in apparent permeability was observed. Data represents mean±s.d. and representative of at least 2 experimental replicates.

FIG. 3A shows representative plots of TK.6 cells treated with an exemplary compound (VII-3), with or without S9 metabolic activation, in accordance with one or more embodiments of the present disclosure. Methyl methanesulfonate, a known genotoxic, alkylating agent was used as a positive control for micronuclei detection.

FIGS. 3B and 3C show quantification of TK.6 micronuclei assay following treatment with various exemplary compounds across a concentration range, in accordance with one or more embodiments of the present disclosure.

FIG. 3D shows normalized β-galactosidase activity (as quantified via absorbance) from the SOS chromotest using a known genotoxin (4-NQ; 4-nitroquinoline-1-oxide) and exemplary compounds at varying concentrations, in accordance with one or more embodiments of the present disclosure. The SOS chromotest is a well-established bacteria-based test for genotoxicity.

FIG. 3E shows normalized reactive oxygen species (ROS) activity in follicle dermal papilla cells treated with 5 μg/mL exemplary compounds relative to vehicle control (0.1% v/v DMSO) after 24 hr.

FIG. 3F shows normalized caspase 3/7 activity in HepG2 cells, an immortalized liver cell line commonly used to study apoptosis induced by small molecules. Cells were treated with either the exemplary compounds or vehicle control containing correspondingly % v/v-matched amounts of DMSO spanning a >2-log concentration range. Data represents mean±s.d. and representative of at least 2 experimental replicates.

FIG. 4A shows normalized ARE-luciferase activity using a known sensitizing compound (cinnamic aldehyde) and exemplary compounds, in accordance with one or more embodiments of the present disclosure.

FIGS. 4B-4E show in vitro dendritic cell sensitization test, in accordance with one or more embodiments of the present disclosure. Dendritic cell activation is widely-associated with downstream immunogenicity. CD14+ cells from human donor peripheral mononuclear cells were harvested and differentiated them into immature monocyte-derived DCs using granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4), then treated with the exemplary compounds. Killed E. Coli and TNF-α were used as positive controls. FIG. 4B shows representative plots showing change in HLA-DR expression. Expression of CD80 (FIG. 4C), PDL-1 (FIG. 4D), and CD141 (FIG. 4E) was quantified via mean fluorescence intensity (MFI) following dosing with various exemplary compounds. Data represents mean±s.d. and representative of at least 2 experimental replicates.

FIG. 5A shows representative images of ex vivo epithelial samples of epidermal tissue surrounding hair follicles 24 hr following treatment. Samples were stained for Caspase-3 (red) and with DAPI (cyan). Inset shows representative image of ex vivo skin model.

FIG. 5B shows average corrected fluorescence of cells stained for caspase-3. Images and data are representative of tissues derived from n=2 donors.

FIG. 6 shows exemplary photographs of subjects' hair in clinical consumer perception study. Photographs were taken after 6 weeks. Subjects were female and ranged in age from 27-65 years. Subjects used a simple, water-based formula containing an exemplary compound (at 0.02% v/v) every 2 days in the morning or night on dry or towel-dried hair. Approximately 2 mL was applied directly to the hairline. No randomization was required for the study and subjects were blinded to the name of the test material.

FIGS. 7A and 7B show normalized proliferation follicle papilla cell proliferation after 48 hr following treatment with the exemplary compound (VII-3) pre-treated across a range of pH conditions (FIG. 7A) and temperature conditions (FIG. 7B). Data represents mean±s.d. and representative of n=2 donors.

DETAILED DESCRIPTION OF THE INVENTION

While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

In certain aspects, the disclosure provides methods for preventing or treating hair loss or hair thinning (whether or not a diagnosis of hair loss or hair thinning has been made).

Definitions

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.

As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.

The term “C_(x-y)” or “C_(x)-C_(y)” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term “C₁₋₆alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons.

The terms “C_(x-y)alkenyl” and “C_(x-y)alkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.

The term “aryl” refers to an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system. The aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.

The term “cycloalkyl” refers to a saturated ring in which each atom of the ring is carbon. Cycloalkyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, spiro bicycles, and 5- to 12-membered bridged rings. In certain embodiments, a cycloalkyl comprises three to ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms. The cycloalkyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The term “halo” or, alternatively, “halogen” or “halide,” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

The term “haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-chloromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the haloalkyl radical is optionally further substituted as described herein.

The term “heterocycle” as used herein refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 5- to 12-membered spiro bicycles, and 5- to 12-membered bridged rings. A bicyclic heterocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. In an exemplary embodiment, an aromatic ring, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, morpholine, piperidine or cyclohexene. A bicyclic heterocycle includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. A bicyclic heterocycle further includes spiro bicylic rings e.g., 5 to 12-membered spiro bicycles.

“Heteroaryl” or “aromatic heterocycle” refers to a radical derived from a heteroaromatic ring radical that comprises one to eleven carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, and S. As used herein, the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems rings wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hückel theory. The heteroatom(s) in the heteroaryl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl. Examples of heteroaryls include, but are not limited to, pyridine, pyrimidine, oxazole, furan, pyran, thiophene, isoxazole, benzimidazole, benzthiazole, and imidazopyridine. An “X-membered heteroaryl” refers to the number of endocylic atoms, i.e., X, in the ring. For example, a 5-membered heteroaryl ring or 5-membered aromatic heterocycle has 5 endocyclic atoms, e.g., triazole, oxazole, thiophene, etc.

The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH or NH₂ of a compound. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds.

In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (═O), thioxo (═S), cyano (—CN), nitro (—NO₂), imino (═N—H), oximo (═N—OH), hydrazino (═N—NH₂), —R^(bb)—OR^(aa), —R^(bb)—OC(O)—R^(aa), —R^(bb)—OC(O)—OR^(aa), —R^(bb)—OC(O)—N(R^(aa))₂, —R^(bb)—N(R^(aa))₂, —R^(bb)—C(O)R^(aa), —R^(bb)—C(O)OR^(aa), —R^(bb)—C(O)N(R^(aa))₂, —R^(bb)—O—R^(bb)—C(O)N(R^(aa))₂, —R^(bb)—N(R^(aa))C(O)OR^(aa), —R^(bb)—N(R^(aa))C(O)R^(aa), —R^(bb)—N(R^(aa))S(O)_(t)R^(aa) (where t is 1 or 2), —R^(bb)—S(O)_(t)R^(aa) (where t is 1 or 2), —R^(bb)—S(O)_(t)OR^(aa) (where t is 1 or 2), and —R^(bb)—S(O)_(t)N(R^(aa))₂ (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (═O), thioxo (═S), cyano (—CN), nitro (—NO₂), imino (═N—H), oximo (═N—OH), hydrazine (═N—NH₂), —R^(bb)—OR^(aa), —R^(bb)—OC(O)—R^(aa), —R^(bb)—OC(O)—OR^(aa), —R^(bb)—OC(O)—N(R^(aa))₂, —R^(bb)—N(R^(aa))₂, —R^(bb)—C(O)R^(aa), —R^(bb)—C(O)OR^(aa), —R^(bb)—C(O)N(R^(aa))₂, —R^(bb)—O—R^(bb)—C(O)N(R^(aa))₂, —R^(bb)—N(R^(aa))C(O)OR^(aa), —R^(bb)—N(R^(aa))C(O)R^(aa), —R^(bb)—N(R^(aa))S(O)_(t)R^(aa) (where t is 1 or 2), —R^(bb)—S(O)_(t)R^(aa) (where t is 1 or 2), —R^(bb)—S(O)_(t)OR^(aa) (where t is 1 or 2) and —R^(bb)—S(O)_(t)N(R^(aa))₂ (where t is 1 or 2); wherein each R^(aa) is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each R^(aa), valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (═O), thioxo (═S), cyano (—CN), nitro (—NO₂), imino (═N—H), oximo (═N—OH), hydrazine (═N—NH₂), —R^(bb)—OR^(aa), —R^(bb)—OC(O)—R^(aa), —R^(bb)—OC(O)—OR^(aa), —R^(bb)—OC(O)—N(R^(aa))₂, —R^(bb)—N(R^(aa))₂, —R^(bb)—C(O)R^(aa), —R^(bb)—C(O)OR^(aa), —R^(bb)—C(O)N(R^(aa))₂, —R^(bb)—O—R^(bb)—C(O)N(R^(aa))₂, —R^(bb)—N(R^(aa))C(O)OR^(aa), —R^(bb)—N(R^(aa))C(O)R^(aa), —R^(bb)—N(R^(aa))S(O)_(t)R^(aa) (where t is 1 or 2), —R^(bb)—S(O)_(t)R^(aa) (where t is 1 or 2), —R^(bb)—S(O)_(t)OR^(aa) (where t is 1 or 2) and —R^(bb)—S(O)_(t)N(R^(aa))₂ (where t is 1 or 2); and wherein each R^(bb) is independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each R^(cc) is a straight or branched alkylene, alkenylene or alkynylene chain.

Double bonds to oxygen atoms, such as oxo groups, are represented herein as both “═O” and “(O)”. Double bonds to nitrogen atoms are represented as both “═NR” and “(NR)”. Double bonds to sulfur atoms are represented as both “═S” and “(S)”.

The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

In certain embodiments, the term “cosmetically acceptable salt” means any salt that is cosmetically tolerated if used appropriately for a cosmetic treatment especially if used on or applied to humans and/or mammals. In certain embodiments, these salts include, but are not restricted to the salts used to form base addition salts, either inorganic, such as for example and in a non-limiting sense, lithium, sodium, potassium, calcium, magnesium or aluminium, among others, or organic such as for example and in a non-limiting sense, ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, arginine, lysine, histidine, or piperazine among others; or acid addition salts, either organic, such as for example and in a non-limiting sense, acetate, citrate, lactate, malonate, maleate, tartrate, fumarate, benzoate, aspartate, glutamate, succinate, oleate, trifluoroacetate, oxalate, pamoate or gluconate among others, or inorganic, such as for example and in a non-limiting sense, chloride, sulfate, borate, or carbonate among others.

A “cosmetically effective amount” as used herein refers to the amount of a compound sufficient to improve the outward physical appearance of a subject. It is to be understood that a “cosmetically effective” amount can vary from subject to subject, due to numerous factors including for example age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician.

The phrase “cosmetically acceptable excipient” or “cosmetically acceptable carrier” as used herein comprises as a pharmaceutical cream base, an oil-in-water emulsion, a water-in-oil emulsion, a gel, or the like. The skilled artisan will understand that the appropriate carriers typically will contain ingredients, such as those typically found in the cosmetic and cosmeceutical fields: oils, waxes or otherstandard fatty substances, or conventional gelling agents and/or thickeners; emulsifiers; moisturizing agents; emollients; sunscreens; hydrophilic or lipophilic active agents; agents for combatting free radicals; preservatives; basifying or acidifying agents; fragrances; surfactants; fillers; natural products or extracts of natural product, such as aloe or green tea extract; vitamins; or coloring materials.

The term “in vivo” generally refers to an event that takes place in a subject's body.

The term “in vitro” generally refers to an event that takes places outside of a subject's body. For example, an in vitro assay encompasses any assay run outside of a subject. In vitro assays encompass cell-based assays in which cells alive or dead are employed. In vitro assays also encompass a cell-free assay in which no intact cells are employed.

“Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optionally substituted aryl” means that the aryl group may or may not be substituted and that the description includes both substituted aryl groups and aryl groups having no substitution.

“Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye, colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

Compounds and Compositions

The present disclosure provides compounds, salts thereof, and compositions and formulations thereof, for hair treatment. The compounds or salts thereof may have a structural formula (I), (II), (III), (IV), (V), (VI), (VII_(A)), (VII_(B)), or (VIII). The compounds or salts thereof may be selected from those forth in Tables 1-10, or any subset thereof. The compounds and salts thereof disclosed herein may be used in method(s) of the disclosure.

Compounds of Formula (VII_(B)) and Subformulae Thereof

In certain aspects, disclosed herein is a compound having a structure of Formula (VII_(B)):

or a salt thereof, wherein:

-   -   B is aryl or heteroaryl, wherein the heteroaryl is selected from         pyridine, pyrimidine, oxazole, furan, pyran, thiophene,         isoxazole, benzimidazole, benzthiazole, and imidazopyridine;     -   R¹ is selected from hydrogen, C₁₋₆ alkyl or C₁₋₆ haloalkyl,         —S-alkyl, —S-haloalkyl, —S(O)(O)R^(a); wherein R^(a) is selected         from the group consisting of hydrogen, C₁₋₆ alkyl, or C₁₋₆         haloalkyl;     -   R² is selected from —OH, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —SR^(b),         —NH₂, alkylamino, and imino, wherein R² is selected from the         group consisting of hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and

and R³ and R⁴ is independently selected from the group consisting of hydrogen, C₁₋₆ alkyl or C₁₋₆ haloalkyl.

In some embodiments of a compound having structural Formula (VII_(B)) (or a salt thereof), B is heteroayl. In some embodiments, the heteroaryl is furan. In some embodiments, R¹ is hydrogen or S(O)(O)R^(a). In some embodiments, R^(a) is methyl or ethyl. In some embodiments, R² is imino or —SR^(b). In some embodiments, R^(b) is methyl or

In some embodiments, R³ is hydrogen or ethyl. In some embodiments, R⁴ is hydrogen.

In some embodiments, a compound having structural Formula (VII_(B)) is selected from those set forth in Table 1, and salts thereof.

TABLE 1 Exemplary compounds of Group I Molecular ID# Chemical Structure Chemical Name Weight VII-2

1H-1,2,4-Triazol-5- amine, 1- (ethylsulfonyl)-3- (2-furanyl)- 242.260 VII-3

1H-1,2,4-Triazole, 3-(2-furanyl)-1- (methylsulfonyl)-5- (methylthio)- 259.312 VII-4

Ethanone, 2-[[4- ethyl-5-(2-furanyl)- 4H-1,2,4-triazol-3- yl]thio]-1-[4-(l- pyrrolidinylsulfonyl) phenyl]- 446.554

Compounds of Formula (I) and Subformulae Thereof

In certain aspects, disclosed herein is a compound having a structure of Formula (VII_(A)):

or a salt thereof, wherein:

-   -   A is aryl or heteroaryl, wherein the heteroaryl is selected from         pyridine, pyrimidine, oxazole, furan, pyran, thiophene,         isoxazole, benzimidazole, benzthiazole, and imidazopyridine;     -   R¹ is C₁₋₆ alkyl or C₁₋₆ haloalkyl; and

R² is —C(O)OH, —C(O)O-alkyl, or —C(O)O-haloalkyl.

In some embodiments of a compound having structural Formula (VII_(A)) (or a salt thereof), A is aryl. In some embodiments, the aryl is phenyl. In some embodiments, R¹ is C₁₋₆ alkyl. In some embodiments, the C₁₋₆ alkyl is methyl. In some embodiments, R² is —C(O)O-alkyl.

In some embodiments, a compound having structural Formula (VII_(A)) is the compound shown in Table 2, or a salt thereof.

TABLE 2 Exemplary compound of Group II ID# Chemical Structure Chemical Name Molecular Weight VII-1

5-Pyrimidinecarboxylic acid, 1,4-dihydro-6- (methylsulfonyl)-4- oxo-2-phenyl-, methyl ester 308.315

Compounds of Formula (I) and Subformulae Thereof

In certain aspects, disclosed herein is a compound having a structure of Formula (VIII):

or a salt thereof, wherein:

-   -   m is 0, 1, or 2; and         R^(x) is each independently C₁₋₆ alkyl, C₅₋₈ aryl, C₁₋₆         haloalkyl, alkylaryl, or haloalkylaryl.

In some embodiments of a compound having structural Formula (VIII) (or a salt thereof), m is 2. In some embodiments, R^(x) is each independently methyl or phenyl.

In some embodiments, a compound having structural Formula (VIII) is the compound shown in Table 3, or a salt thereof.

TABLE 3 Exemplary compound of Group III ID# Chemical Structure Chemical Name Molecular Weight VII-25

2,4- Imidazolidinedione, 5-methyl-3-[(4-oxo- 4H-pyrido[1,2-a] pyrimidin-2-yl) methyl]-5-phenyl- 348.362

Compounds of Formula (I) and Subformulae Thereof

In certain aspects, disclosed herein is a compound having a structure of Formula (I):

or a salt thereof, wherein:

Y¹ is O or S;

Y² is O or S;

Y³ is O or S;

R¹ is selected from H, alkyl, haloalkyl, alkenyl, haloalkenyl, aryl (e.g., phenyl), and aralkyl (e.g., benzyl), wherein the aryl or aralkyl is optionally substituted with one or more substituents independently selected from halogen, alkyl, alkoxy, and haloalkoxy;

R² is selected from H, alkyl, alkenyl, haloalkyl, and haloalkenyl;

A is aryl (e.g., phenyl) or heteroaryl (e.g., pyrimidinyl);

p is 0, 1, 2, or 3; and

R^(x) is each independently selected from halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, —OH, alkoxy, haloalkoxy, —O-alkylene-C(O)OH, nitro, —NH₂, alkylamino, dialkylamino, and haloalkylamino; or,

alternatively, two R^(x) together with the atoms to which they are attached to form (e.g., C₄-C₆) cycloalkyl or (e.g., 5- or 6-membered) heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more substituents independently selected from halogen, alkyl, and haloalkyl.

In some embodiments of a compound having structural Formula (I) (or a salt thereof), R² is selected from (e.g., C₁₋₆, such as C₁₋₄) alkyl, (e.g., C₁₋₆, such as C₁₋₄) alkenyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkyl, and (e.g., C₁₋₆, such as C₁₋₄) haloalkenyl. In some embodiments, Y¹ is S. In some embodiments, Y³ is S. In some embodiments, A is

wherein Q¹ and Q² are each independently CH or N. In some embodiments, A is

In some embodiments, the compound having a structural Formula (I) (or the salt thereof) has a structural Formula (I_(A1)) or (I_(A2)):

or a salt thereof, wherein:

R^(x1), R^(x2), R^(x3), R^(x1′), R^(x2′), and R^(x3′) are each independently selected from halogen, (e.g., C₁₋₆, such as C₁₋₄) alkyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkyl, (e.g., C₁₋₆, such as C₁₋₄) alkenyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkenyl, —OH, (e.g., C₁₋₆, such as C₁₋₄) alkoxy, (e.g., C₁₋₆, such as C₁₋₄) haloalkoxy, —O-alkylene-C(O)OH, nitro, —NH₂, (e.g., C₁₋₆, such as C₁₋₄) alkylamino, (e.g., C₁₋₆, such as C₁₋₄) dialkylamino, and (e.g., C₁₋₆, such as C₁₋₄) haloalkylamino.

In some embodiments of a compound having structural Formula (I_(A1)) or (I_(A2)) (or a salt thereof), R² is selected from (e.g., C₁₋₆, such as C₁₋₄) alkyl, (e.g., C₁₋₆, such as C₁₋₄) alkenyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkyl, and (e.g., C₁₋₆, such as C₁₋₄) haloalkenyl. In some embodiments, Y¹ is S. In some embodiments, Y³ is S. In some embodiments, A is

wherein Q¹ and Q² are each independently CH or N. In some embodiments, A is

In some embodiments, the compound having a structural Formula (I) (or the salt thereof) has a structural Formula (I_(B1)):

wherein:

R^(x4) and R^(x5) are each independently selected from halogen, (e.g., C₁₋₆, such as C₁₋₄) alkyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkyl, (e.g., C₁₋₆, such as C₁₋₄) alkenyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkenyl, —OH, (e.g., C₁₋₆, such as C₁₋₄) alkoxy, (e.g., C₁₋₆, such as C₁₋₄) haloalkoxy, —O-alkylene-C(O)OH, nitro, —NH₂, (e.g., C₁₋₆, such as C₁₋₄) alkylamino, (e.g., C₁₋₆, such as C₁₋₄) dialkylamino, and (e.g., C₁₋₆, such as C₁₋₄) haloalkylamino.

In some embodiments of a compound having structural Formula (I_(B1)) (or a salt thereof), R² is selected from (e.g., C₁₋₆, such as C₁₋₄) alkyl, (e.g., C₁₋₆, such as C₁₋₄) alkenyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkyl, and (e.g., C₁₋₆, such as C₁₋₄) haloalkenyl. In some embodiments, Y¹ is S. In some embodiments, Y³ is S. In some embodiments, A is

wherein Q¹ and Q² are each independently CH or N. In some embodiments, A is

In some embodiments, the compound having a structural Formula (I) (or the salt thereof) has a structural Formula (I_(B2)):

wherein:

R^(x6) and R^(x7) are each independently selected from halogen, (e.g., C₁₋₆, such as C₁₋₄) alkyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkyl, (e.g., C₁₋₆, such as C₁₋₄) alkenyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkenyl, —OH, (e.g., C₁₋₆, such as C₁₋₄) alkoxy, (e.g., C₁₋₆, such as C₁₋₄) haloalkoxy, —O-alkylene-C(O)OH, nitro, —NH₂, (e.g., C₁₋₆, such as C₁₋₄) alkylamino, (e.g., C₁₋₆, such as C₁₋₄) dialkylamino, and (e.g., C₁₋₆, such as C₁₋₄) haloalkylamino; or,

alternatively, R^(x6) and R^(x7) together with the atoms to which they are attached to form cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more substituents independently selected from halogen, (e.g., C₁₋₆, such as C₁₋₄) alkyl, and (e.g., C₁₋₆, such as C₁₋₄) haloalkyl.

In some embodiments of a compound having structural Formula (I_(B2)) (or a salt thereof), R² is selected from (e.g., C₁₋₆, such as C₁₋₄) alkyl, (e.g., C₁₋₆, such as C₁₋₄) alkenyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkyl, and (e.g., C₁₋₆, such as C₁₋₄) haloalkenyl. In some embodiments, Y¹ is S. In some embodiments, Y³ is S. In some embodiments, A is

wherein Q¹ and Q² are each independently CH or N. In some embodiments, A is

In some embodiments, the compound having a structural Formula (I) (or the salt thereof) has a structural Formula (I_(C1)) or (I_(C2)):

wherein:

R^(x8) and R^(x9) are each independently selected from halogen, (e.g., C₁₋₆, such as C₁₋₄) alkyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkyl, (e.g., C₁₋₆, such as C₁₋₄) alkenyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkenyl, —OH, (e.g., C₁₋₆, such as C₁₋₄) alkoxy, (e.g., C₁₋₆, such as C₁₋₄) haloalkoxy, —O-alkylene-C(O)OH, nitro, —NH₂, (e.g., C₁₋₆, such as C₁₋₄) alkylamino, (e.g., C₁₋₆, such as C₁₋₄) dialkylamino, and (e.g., C₁₋₆, such as C₁₋₄) haloalkylamino.

In some embodiments of a compound having structural Formula (I_(C1)) or (I_(C2)) (or a salt thereof), R² is selected from (e.g., C₁₋₆, such as C₁₋₄) alkyl, (e.g., C₁₋₆, such as C₁₋₄) alkenyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkyl, and (e.g., C₁₋₆, such as C₁₋₄) haloalkenyl. In some embodiments, Y¹ is S. In some embodiments, Y³ is S. In some embodiments, A is

wherein Q¹ and Q² are each independently CH or N. In some embodiments, A is

In some embodiments, a compound having structural Formula (I) is selected from those set forth in Table 4, and salts thereof.

TABLE 4 Exemplary compounds of Group IV Molecular ID# Chemical Structure Chemical Name Weight I-1

2,4,6(1H,3H,5H)- Pyrimidinetrione, 5-[[4- hydroxy-3-methoxy-5- (2-propen-1-yl)phenyl] methylene]-1-[4-(1- methylethyl)phenyl]- 420.465 I-2

2,4,6(1H,3H,5H)- Pyrimidinetrione, 1-(3, 5-dimethylphenyl)-5- [[3-ethoxy-4-hydroxy- 5-(2-propen-1-yl) phenyl]methylene]- 420.465 I-3

2,4,6(1H,3H,5H)- Pyrimidinetrione, 1-(3, 5-dimethylphenyl)-5- [[4-hydroxy-3- methoxy-5-(2-propen- 1-yl)phenyl]methylene]- 406.438 I-4

2,4,6(1H,3H,5H)- Pyrimidinetrione, 1-(3, 4-dimethylphenyl)-5- [[4-hydroxy-3- methoxy-5-(2-propen- 1-yl)phenyl]methylene] 406.438 I-5

2,4,6(1H,3H,5H)- Pyrimidinetrione, 5-[(4- hydroxy-3,5- dimethoxyphenyl) methylene]-1- (phenylmethyl)- 382.372 I-6

2,4,6(1H,3H,5H)- Pyrimidinetrione, 5-[(2, 4-dimethoxyphenyl) methylene]-1-(2- propen-1-yl)- 316.313 I-7

2,4,6(1H,3H,5H)- Pyrimidinetrione, 5-[[3- methoxy-4-(2-propen- 1-yloxy)phenyl] methylene]-1-(2- propen-1-yl)- 342.351 I-8

4,6(1H,5H)- Pyrimidinedione, 5-[[3- ethoxy-4-hydroxy-5-(2- propen-1-yl)phenyl] methylene]dihydro-2- thioxo- 332.381 I-9

4,6(1H,5H)- Pyrimidinedione, dihydro-5-[[4-hydroxy- 3-methoxy-5-(2- propen-1-yl)phenyl] methylene]-2-thioxo- 318.354 I-10

4,6(1H,5H)- Pyrimidinedione, 5-[[4- ethoxy-3-methoxy-5- (2-propen-1-yl)phenyl] methylene]dihydro-1- methyl-2-thioxo- 360.435 I-1I

2,4,6(1H,3H,5H)- Pyrimidinetrione, 5-[(2, 4-dimethoxyphenyl) methylene]-1-methyl-, (5E)- 290.275 I-12

2,4,6(1H,3H,5H)- Pyrimidinetrione, 5-[(1- butyl-2,3-dihydro-1H- indol-5-yl)methylene]- 1-methyl- 327.384 I-13

2,4,6(1H,3H,5H)- Pyrimidinetrione, 5-[[2- (dimethylamino)-5- pyrimidinyl]methylene]- 1-methyl- 275.268 I-14

Acetic acid, 2-[3- [(tetrahydro-1-methyl- 2,4,6-trioxo-5(2H)- pyrimidinylidene) methyl]phenoxy]- 304.258 I-15

2,4,6(1H,3H,5H)- Pyrimidinetrione, 5-[(2- hydroxy-3-methoxy-5- nitrophenyl)methylene]- 1-methyl- 321.245 I-16

2,4,6(1H,3H,5H)- Pyrimidinetrione, 5-[[4- hydroxy-3-methoxy-5- (2-propen-1-yl)phenyl] methylene]-1-methyl- 316.313 I-17

4,6(1H,5H)- Pyrimidinedione, dihydro-5-[[4-hydroxy- 3-methoxy-5-(2- propen-1-yl)phenyl] methylene]-1-(4- methoxyphenyl)-2- thioxo- 424.478 I-18

4,6(1H,5H)- Pyrimidinedione, 5-[[3- ethoxy-4-hydroxy-5-(2- propen-1-yl)phenyl] methylene]dihydro-1- (2-methoxyphenyl)-2- thioxo- 438.505

Compounds and Salts of Formula (II)

In certain aspects, disclosed herein is a compound represented by Formula (II):

or a salt thereof, wherein:

R^(y) is each independently alkyl or haloalkyl;

m is 0, 1, or 2;

L¹ is selected from bond, —O—, —S—, —N(R^(a1))—, —C(O)—, —C(O)-alkylene-, —C(O)-alkylene-O—, -alkylene-C(O)—, -alkylene-C(O)—O—, —C(O)O—, —OC(O)—, —C(O)N(R^(a2))—, —N(R^(a3))C(O)—, —N(R^(a4))C(O)N(R^(a5))—, —N(R^(a6))C(O)O—, —OC(O)N(R^(a7))—, —S(O)₂—, —OS(O)—, —S(O)₂—, —S(O)—, —OS(O)₂—, —S(O)₂O—, —N(R^(a8))S(O)₂—, —S(O)₂N(R^(a9))—, —N(R^(a10))S(O)—, —S(O)N(R^(a11))—, —N(R^(a12))S(O)₂N(R^(a13))—, and N(R^(a14))S(O)N(R^(a15))—; and

R¹ is selected from H, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, cycloalkyl, alkylcycloalkyl, halocycloalkyl, aryl (e.g., phenyl), alkylaryl, heteroaryl, —O-aryl, —O-alkylaryl, and —O— heteroaryl.

In some embodiments, the compound having a structural Formula (II) (or the salt thereof) has a structural Formula (II_(A)):

In certain embodiments, for a compound or salt of Formula (II) or (II_(A)), R^(y) is C₁-C₆ (e.g., C₁-C₄) alkyl (e.g., methyl). In some embodiments, m is 1. In some embodiments, L¹ is selected from —C(O)—, —C(O)-alkylene-O—, and —S(O)₂—. In some embodiments, R¹ is selected from alkyl, cycloalkyl, aryl, alkylaryl, —O-aryl, and —O-alkylaryl.

In some embodiments, a compound having structural Formula (II) is selected from those set forth in Table 5, and salts thereof.

TABLE 5 Exemplary compounds of Group V ID # Chemical Structure Chemical Name Molecular Weight II-1

Methanone, cyclohexyl[4-[4- (4-methylphenyl)- 1-phthalazinyl]-1- piperazinyl]- 414.553 II-2

Methanone, (4- methylphenyl)[4- [4-(4- methylphenyl)-1- phthalazinyl]-1- piperazinyl]- 422.532 II-3

Phthalazine, 1-(4- methylphenyl)-4- [4- (methylsulfonyl)- 1-piperazinyl]- 382.489 II-4

1-Propanone, 1-[4- [4-(4- methylphenyl)-1- phthalazinyl]-1- piperazinyl]- 360.461 II-5

Ethanone, 2-(4- methylphenoxy)-1- [4-[4-(4- methylphenyl)-1- phthalazinyl]-1- piperazinyl]- 452.558 II-6

1-Butanone, 1-[4- [4-(4- methylphenyl)-1- phthalazinyl]-1- piperazinyl]- 374.488

In certain aspects, disclosed herein is a compound represented by Formula (III):

or a salt thereof, wherein:

A is aryl or heteroaryl;

p is 0, 1, or 2;

R^(y) is each independently alkyl or haloalkyl;

q is 0, 1, or 2;

Rz is each independently alkyl or haloalkyl; and

R¹ and R² are each independently selected from H, optionally substituted aryl, —NH—C(O)—NH— cycloalkyl (e.g., adamantyl), —C(O)—NH-cycloalkyl, and —NH—C(O)-cycloalkyl; or,

alternatively, R¹ and R² join together with the nitrogen atom to which they are attached to form N-heterocyclyl (e.g., piperazinyl) or —N═R^(c), wherein R^(c) is an optionally substituted aryl or optionally substituted heteroaryl.

In certain embodiments, for a compound or salt of Formula (III), R¹ and R² join together with the nitrogen atom to which they are attached to form

wherein R^(x) is selected from alkyl, haloalkyl, -alkylene-OH, -alkylene-O-alkyl, -alkylene-aryl, and -alkylene-arylene-alkyl. In some embodiments, R¹ and R² join together with the nitrogen atom to which they are attached to form

In some embodiments, R¹ and R² join together with the nitrogen atom to which they are attached to form an optionally substituted piperazinyl. In some embodiments, A is pyridinyl

In some embodiments, a compound having structural Formula (III) is selected from those set forth in Table 6, and salts thereof.

TABLE 6 Exemplary compounds of Group VI Molecular ID # Chemical Structure Chemical Name Weight III-1

Methanone, [4-(4- methoxyphenyl)-1- piperazinyl][2-(2- thienyl)-4-quinolinyl]- 429.545 III-2

4- Quinolinecarboxamide, 6-methyl-N-[1-[(3- methylphenyl)methyl]- 1H-1,2,4-triazol-3-yl]- 2-(3-pyridinyl)- 434.503 III-3

4- Quinolinecarboxamide, 2-(3,4- dimethylphenyl)-N- [4-[(3,5-dimethyl-1H- pyrazol-1-yl)methyl] phenyl]- 460.581 III-4

4- Quinolinecarboxamide, N-[5-(2-ethoxyethyl)- 1,3,4-thiadiazol-2-yl]- 2-phenyl- 404.495 III-5

4-Quinolinecarboxylic acid, 2-(2,4- dimethylphenyl)-, 2- [(tricyclo[3.3.1.1^(3,7)] dec-1-ylamino) carbonyl]hydrazide 468.601

In certain aspects, disclosed herein is a compound represented by Formula (IV):

or a salt thereof, wherein:

A is heteroaryl;

q is 0, 1, 2, or 3; and

R^(x) is selected from alkyl, haloalkyl, alkoxyl, haloalkoxyl, —SH, alkylthio, aryl, and alkoxylaryl.

In some embodiments, a compound having structural Formula (IV) is selected from those set forth in Table 7, and salts thereof.

TABLE 7 Exemplary compounds of Group VII Molecular ID # Chemical Structure Chemical Name Weight IV-1

2H-1-Benzopyran-2- one, 4-[[[5-[(1,1- dimethylethyl)amino]-1, 3,4-thiadiazol-2-yl]thio] methyl]-7-hydroxy- 363.464 IV-2

2H-1-Benzopyran-2- one, 7-hydroxy-4-[[[5- (methylthio)-1,3,4- thiadiazol-2-yl]thio] methyl]- 338.435 IV-3

4(3H)-Quinazolinone, 2- [[(7-hydroxy-2-oxo-2H- 1-benzopyran-4-yl) methyl]thio]-3-(2- methoxyphenyl)- 458.495 IV-4

Thieno[2,3-d]pyrimidin- 4(1H)-one, 2-[[(7- hydroxy-2-oxo-2H-1- benzopyran-4-yl)methyl] thio]-6-methyl-5-(2- methylbutyl)- 442.562

In certain aspects, disclosed herein is a compound represented by Formula (V):

or a salt thereof, wherein:

R¹ is H or optionally substituted aryl;

R^(m) and R^(n) join together with the nitrogen atom to which they are attached to form N-heterocyclyl, wherein the N-heterocyclyl is optionally substituted with one or more substituents selected from alkyl, —S(O)H, —S(O)₂H, —S(O)-alkyl, and —S(O)₂-alkyl;

Q₁ is NR^(a1), CR^(b1)R^(b2), or S;

Q₃ is N or CR^(b3); and

Q₂ is NR^(a2) or CR^(b4)R^(b5); wherein:

R^(a1), R^(a2), R^(b1), R^(b2), R^(b3), R^(b4), and R^(b5) are each independently selected from H, optionally substituted aryl, optionally substituted alkylaryl, and optionally substituted arylalkyl.

In certain embodiments, for a compound or salt of Formula (V), Q¹ is CR^(b1)R^(b2) or S. In some embodiments, Q³ is CR^(b3).

In some embodiments, a compound having structural Formula (V) is selected from those set forth in Table 8, and salts thereof.

TABLE 8 Exemplary compounds of Group VIII Molecular ID # Chemical Structure Chemical Name Weight V-1

1H-Pyrazolo[3,4-d] pyrimidine, 1-[(4- methylphenyl)methyl]- 4-(1-pyrrolidinyl)- 293.374 V-2

1H-Pyrazolo[3,4-d] pyrimidine, 1-(2,4- dimethylphenyl)-4-(1- piperidinyl)- 307.401 V-3

Thieno[2,3-d] pyrimidine, 4-(2- methyl-1-piperidinyl)-2, 6-diphenyl- 385.536 V-4

5H-Pyrrolo[3,2-d] pyrimidine, 4-[4- (ethylsulfonyl)-1- piperazinyl]- 295.368

In certain aspects, disclosed herein is a compound represented by Formula (VI):

or a salt thereof, wherein:

L⁰ is selected from —C(O)—, —O—, —S—, —C(O)O—, —OC(O)—, —S(O)—, —S(O)₂—, —NH—, and

wherein L¹ is selected from —C(O)—, —O—, —S—, —C(O)O—, —OC(O)—, —S(O)—, —S(O)₂—, and —NH—;

p, q, and m are each independently 0, 1, or 2;

Rx, Ry, and Rz are each independently selected from alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, —OH, —C(O)OH, or -alkylene-C(O)OH;

A is aryl or heteroaryl;

L² is alkylene, —C(O)—, —O—, —S—, —C(O)O—, —OC(O)—, —S(O)—, —S(O)₂—, —N(H)S(O)₂—, —S(O)₂N(H)—, -alkylene-N(H)S(O)₂—, —S(O)₂N(H)-alkylene-, —NH—, —N═, and —CH═N—N═; and

B is an optionally substituted aryl or optionally substituted heteroaryl.

In certain embodiments, for a compound or salt of Formula (VI), L⁰ is

In some embodiments, A is phenyl or piperazinyl. In some embodiments, B is selected from

In some embodiments, L² is selected from alkylene, —S(O)₂N(H)-alkylene-, and —CH═N—N═. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, q is 0. In some embodiments, m is 0. In some embodiments, m is 2. In some embodiments, R^(x) is each independently cyano, alkyl, alkoxy, and nitro. In some embodiments, R^(z) is each independently —OH, —C(O)OH, or -alkylene-C(O)OH.

In some embodiments, a compound having structural Formula (VI) is selected from those set forth in Table 9, and salts thereof.

TABLE 9 Exemplary compounds of Group IX Molecular ID # Chemical Structure Chemical Name Weight VI-1

Methanone, [4-(1,3- benzodioxol-5- ylmethyl)-1- piperazinyl][1- (phenylsulfonyl)-4- piperidinyl]- 471.579 VI-2

Benzonitrile, 4-[[4- [[4-(1,3- benzodioxol-5- ylmethyl)-1- piperazinyl]carbonyl]- 1-piperidinyl] sulfonyl]- 496.589 VI-3

Methanone, [4-(1,3- benzodioxol-5- ylmethyl)-1- piperazinyl][1-[(4- methoxy-3- methylphenyl) sulfonyl]-4- piperidinyl]- 515.632 VI-4

Methanone, [4-(2- benzothiazolylmethyl)- 1-piperazinyl][1- [(4-methylphenyl) sulfonyl]-4- piperidinyl]- 498.674 VI-5

Benzenesulfonamide, 4-methoxy-N-[4- [[(2-phenylethyl) amino]sulfonyl] phenyl]- 446.550 VI-6

5-Thiazoleacetic acid, 4,5-dihydro-2- [2-[[4-[[(4- nitrophenyl)sulfonyl] oxy]phenyl] methylene] hydrazinyl]-4-oxo- 478.464

Other Compounds and Salts Thereof

In some embodiments, a compound disclosed herein is selected from those set forth in Table 10, and salts thereof.

TABLE 10 Exemplary compounds of Group X ID Molecular # Chemical Structure Chemical Name Weight VII- 5

1,2,4-Oxadiazole-5- butanamide, N-[4- (aminocarbonyl) phenyl]-3-phenyl- 350.378 VII- 6

1H-Pyrazole-4- carboxylic acid, 1-[4- [[[4-[[(2-methoxy-2- oxoethyl)amino] carbonyl]phenyl] amino]carbonyl] phenyl]-5-methyl-, ethyl ester 464.478 VII- 7

1H-Pyrazole-4- carboxylic acid, 1-[4- [[[4-(ethylsulfonyl) phenyl]amino] carbonyl]phenyl]-5- methyl-, ethyl ester 441.509 VII- 8

1H-Pyrazole-4- carboxylic acid, 5- methyl-1-[3-[[[1-(2- pyrimidinyl)-4- piperidinyl]carbonyl] amino]phenyl]-, ethyl ester 434.500 VII- 9

Spiro[cycloheptane-1, 4′(1′H)-[1,3,5] triazino[1,2-a] benzimidazol]-2′- amine 269.352 VII- 10

1,4-Diazepino[6,5-b] indol-2(1H)-one, 3,4,5, 6-tetrahydro-1-phenyl- 277.327 VII- 11

Spiro[cyclohexane-1, 4′(3′H)-[1,3,5] triazino[1,2-a] benzimidazol-2′- amine 255.325 VII- 12

1H-Isoindole, 2-(3,5- dimethylphenyl)-2,3- dihydro- 223.319 VII- 13

1H-Isoindole-1,3(2H)- dione, 2-cyclohexyl- 3a,4,7,7a-tetrahydro- 233.311 VII- 14

1H-Benzimidazole, 2- [3-(4-methoxyphenyl) propyl]- 266.344 VII- 15

Pyrimidine, 2-[4-[(3- methylphenyl)methyl]- 1-piperazinyl]- 268.364 VII- 16

Benzenesulfonamide, N-(4-methoxyphenyl)- N-[2-[4-(2- methoxyphenyl)-1- piperazinyl]-2- oxoethyl]- 495.601 VII- 17

2H-1,4-Benzothiazin- 3(4H)-one, 2-[2-[4- (diphenylmethyl)-1- piperazinyl]-2- oxoethyl]- 457.599 VII- 18

Piperazine, 1-(1- naphthalenylcarbonyl)- 4-(2-thienylcarbonyl)- (9CI) 350.443 VII- 19

Pregna-1,4-diene-3,20- dione, 21-(3-carboxy- 1-oxopropoxy)-11,17- dihydroxy-, (11β)- 460.523 VII- 20

1,4- Benzenedicarboxamide, N¹,N⁴-diethyl-N¹,N⁴- bis(phenylmethyl)- 400.522 VII- 21

2(1H)- Phthalazineacetamide, N-[2-(1,2-dimethyl- 1H-indol-3-yl)ethyl]-4- [4-methyl-3-(4- morpholinylsulfonyl) phenyl]-1-oxo- 613.740 VII- 22

Benzo[b]thiophene-3- carboxamide, 4,5,6,7- tetrahydro-2-[[2-(4- methoxyphenyl)acetyl] amino]-6-methyl-N-(3- nitrophenyl)- 479.558 VII- 23

Benzoic acid, 3,3′-[[5- (benzoylamino)-1,3- phenylene] bis(carbonylimino)] bis-, dimethyl ester (9CI) 551.555 VII- 24

Benzamide, 4-(1,1- dimethylethyl)-N-[[(2- methyl-5-oxazolo[4,5- b]pyridin-2-ylphenyl) amino]thioxomethyl]- 444.560 VII- 26

Benzo[b]thiophene-3- carboxamide, N-[3,5- dimethyl-1-[(2- methylphenyl)methyl]- 1H-pyrazol-4-yl]- 375.497

In some embodiments, a compound disclosed herein is selected from those (or any subset thereof) set forth in any one or combination of Tables 1 through 10, and salts thereof.

For the synthesis methods of the compounds disclosed herein, see, e.g., WO2009031709 A1; Journal fuer Praktische Chemie (Leipzig), 323 (2), 3030310, 1981; European Journal of Medicinal Chemistry, 47, 138-142, 2012; Pharmaceutical Chemistry Journal, 41, 70-473, 2007; A.M.A.J. Diseases Children, 97, 66-71, 1959; WO2003072099 A1; Chemiker-Zeitung, 111, 159-166, 1987; Journal of Heterocyclic Chemistry, 25(3), 959-968, 1988; and Russian Chemical Bulletin, 52(6), 1386-1398, 2003, each of which is incorporated herein by reference.

Compounds of the present invention also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds described herein. The compounds of the present disclosure that possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.

The compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley and Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.

The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. As well, in some embodiments, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

Compositions

The disclosure provides compositions of compounds disclosed herein and salts thereof. The composition may further comprise at least one additive selected from the group consisting of carriers, excipients, adjuvants, and diluents. The composition is formulated as toner, emulsion, cream, gel, shampoo, soap, serum, spray, or oil.

In some embodiments, the composition is a pharmaceutical composition. The pharmaceutical composition may further comprise at least one additive selected from the group consisting of pharmaceutically acceptable carriers, excipients, adjuvants, and diluents.

In some embodiments, the composition is a cosmetic composition. The cosmetic composition may further comprise at least one additive selected from the group consisting of cosmetically acceptable carriers, excipients, adjuvants, and diluents. The cosmetic composition may be formulated as toner, emulsion, cream, gel, shampoo, soap, serum, spray, or oil.

Methods

Also provided herein include methods for hair treatment with the compound(s) or salt(s) disclosed herein.

In certain aspects, disclosed herein is a method for preventing or treating hair loss or hair thinning, the method comprising administering to a subject in need thereof a composition comprising a compound or salt described herein, or a composition described herein. The compound(s) or salt(s) thereof may have a structural Formula of (I), (II), (III), (IV), (V), (VI), (VII_(A)), (VII_(B)), or (VIII). The compound(s) or salt(s) thereof may be selected from those set forth in any one of Tables 1-10, or any subset thereof, or any combination thereof. A diagnosis of hair loss or hair thinning may or may not have been made. In some embodiments of any method described herein, the subject may have been diagnosed with hair loss or hair thinning. In some embodiments of any method described herein, the subject may not have been diagnosed with hair loss or hair thinning. In some embodiments, the method promotes hair growth, hair restoration or hair thickening of said subject. In some embodiments, the method increases hair density or hair growth rate of said subject. In some embodiments, the hair loss is selected from androgenic alopecia, alopecia areata, androgenetic alopecia, gynecologic alopecia, postpartum alopecia, seborrheic alopecia, non-rigid alopecia, senile alopecia, chemotherapy-induced alopecia, radiation-induced alopecia, male-pattern baldness, female-pattern baldness, cicatricial alopecia, alopecia areata telogen effluvium, traction alopecia, and anagen effluvium. In some embodiments, the hair is scalp hair, eyelash hair, eyebrow hair, or facial hair.

LIST OF EMBODIMENTS

The following list of embodiments of the invention are to be considered as disclosing various features of the invention, which features can be considered to be specific to the particular embodiment under which they are discussed, or which are combinable with the various other features as listed in other embodiments. Thus, simply because a feature is discussed under one particular embodiment does not necessarily limit the use of that feature to that embodiment.

Embodiment 1. A method for preventing or treating hair loss or hair thinning (whether or not a diagnosis of hair loss or hair thinning has been made), the method comprising administering to a subject in need thereof a composition comprising a compound having a structure of Formula (VII_(B)):

or a salt thereof, wherein:

-   -   B is aryl or heteroaryl, wherein the heteroaryl is selected from         pyridine, pyrimidine, oxazole, furan, pyran, thiophene,         isoxazole, benzimidazole, benzthiazole, and imidazopyridine;     -   R¹ is selected from hydrogen, C₁₋₆ alkyl or C₁₋₆ haloalkyl,         —S-alkyl, —S-haloalkyl, —S(O)(O)R^(a); wherein R^(a) is selected         from the group consisting of hydrogen, C₁₋₆ alkyl, or C₁₋₆         haloalkyl;     -   R² is selected from —OH, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —SR,         —NH₂, alkylamino, and imino, wherein R² is selected from the         group consisting of hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and

and

-   -   R³ and R⁴ is independently selected from the group consisting of         hydrogen, C₁₋₆ alkyl or C₁₋₆ haloalkyl.         Embodiment 2. The method of embodiment 1, wherein B is         heteroaryl.         Embodiment 3. The method of embodiment 2, wherein the heteroaryl         is furan.         Embodiment 4. The method of embodiment 1, wherein R¹ is hydrogen         or S(O)(O)R^(a).         Embodiment 5. The method of embodiment 4, wherein R^(a) is         methyl or ethyl.         Embodiment 6. The method of embodiment 1, wherein R² is imino or         —SR^(b).         Embodiment 7. The method of embodiment 6, wherein R^(b) is         methyl or

Embodiment 8. The method of embodiment 1, wherein R³ is hydrogen or ethyl. Embodiment 9. The method of embodiment 1, wherein R⁴ is hydrogen. Embodiment 10. The method of embodiment 1, wherein the compound of Formula (VII_(B)) or the salt thereof is selected from:

Embodiment 11. A method for preventing or treating hair loss or hair thinning (whether or not a diagnosis of hair loss or hair thinning has been made), the method comprising administering to a subject in need thereof a composition comprising a compound having a structure of Formula (VII_(A)):

or a salt thereof, wherein:

-   -   A is aryl or heteroaryl, wherein the heteroaryl is selected from         pyridine, pyrimidine, oxazole, furan, pyran, thiophene,         isoxazole, benzimidazole, benzthiazole, and imidazopyridine;     -   R¹ is C₁₋₆ alkyl or C₁₋₆ haloalkyl; and     -   R² is —C(O)OH, —C(O)O-alkyl, or —C(O)O-haloalkyl.         Embodiment 12. The method of embodiment 11, wherein A is aryl.         Embodiment 13. The method of embodiment 12, wherein the aryl is         phenyl.         Embodiment 14. The method of embodiment 11, wherein R¹ is C₁₋₆         alkyl.         Embodiment 15. The method of embodiment 12, wherein R² is         —C(O)O-alkyl.         Embodiment 16. The method of embodiment 8, wherein the compound         of Formula (VII_(A)) is

or a salt thereof. Embodiment 17. A method for preventing or treating hair loss or hair thinning (whether or not a diagnosis of hair loss or hair thinning has been made), the method comprising administering to a subject in need thereof a composition comprising a compound having a structure of Formula (VIII):

or a salt thereof, wherein:

-   -   m is 0, 1, or 2; and     -   R^(x) is each independently C₁₋₆ alkyl, C₅₋₈ aryl, C₁₋₆         haloalkyl, alkylaryl, or haloalkylaryl.         Embodiment 18. The method of embodiment 17, wherein m is 2.         Embodiment 19. The method of embodiment 17, wherein R^(x) is         each independently methyl or phenyl.         Embodiment 20. The method of embodiment 17, wherein the compound         of Formula (VIII) is

or a salt thereof. Embodiment 21. A method for preventing or treating hair loss or hair thinning (whether or not a diagnosis of hair loss or hair thinning has been made), the method comprising administering to a subject in need thereof a composition comprising a compound having a structure of Formula (I):

or a salt thereof, wherein:

-   -   Y¹ is O or S;     -   Y² is O or S;     -   Y³ is O or S;     -   R¹ is selected from H, alkyl, haloalkyl, alkenyl, haloalkenyl,         aryl (e.g., phenyl), and aralkyl (e.g., benzyl), wherein the         aryl or aralkyl is optionally substituted with one or more         substituents independently selected from halogen, alkyl, alkoxy,         and haloalkoxy;     -   R² is selected from H, alkyl, alkenyl, haloalkyl, and         haloalkenyl;     -   A is aryl (e.g., phenyl) or heteroaryl (e.g., pyrimidinyl);     -   p is 0, 1, 2, or 3; and     -   R^(x) is each independently selected from halogen, alkyl,         haloalkyl, alkenyl, haloalkenyl, —OH, alkoxy, haloalkoxy,         —O-alkylene-C(O)OH, nitro, —NH₂, alkylamino, dialkylamino, and         haloalkylamino; or,

alternatively, two R^(x) together with the atoms to which they are attached to form (e.g., C₄-C₆) cycloalkyl or (e.g., 5- or 6-membered) heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more substituents independently selected from halogen, alkyl, and haloalkyl.

Embodiment 22. The method of embodiment 21, wherein R² is selected from (e.g., C₁₋₆, such as C₁₋₄) alkyl, (e.g., C₁₋₆, such as C₁₋₄) alkenyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkyl, and (e.g., C₁₋₆, such as C₁₋₄) haloalkenyl. Embodiment 23. The method of embodiment 21 or 22, wherein Y¹ is S. Embodiment 24. The method of any one of embodiments 21 to 23, wherein Y³ is S. Embodiment 25. The method of any one of embodiments 21 to 24, wherein A is

wherein Q¹ and Q² are each independently CH or N. Embodiment 26. The method of embodiment 25, wherein A is

Embodiment 27. The method of embodiment 25 or 26, wherein the compound of Formula (I) has a structure of Formula (I_(A1)) or (I_(A2)):

wherein:

R^(x1), R^(x2), R^(x3), R^(x1), R^(x2), and R^(x3) are each independently selected from halogen, (e.g., C₁₋₆, such as C₁₋₄) alkyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkyl, (e.g., C₁₋₆, such as C₁₋₄) alkenyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkenyl, —OH, (e.g., C₁₋₆, such as C₁₋₄) alkoxy, (e.g., C₁₋₆, such as C₁₋₄) haloalkoxy, —O-alkylene-C(O)OH, nitro, —NH₂, (e.g., C₁₋₆, such as C₁₋₄) alkylamino, (e.g., C₁₋₆, such as C₁₋₄) dialkylamino, and (e.g., C₁₋₆, such as C₁₋₄) haloalkylamino.

Embodiment 28. The method of embodiment 25 or 26, wherein the compound of Formula (I) has a structure of Formula (I_(B1)):

wherein:

R^(x4) and R^(x5) are each independently selected from halogen, (e.g., C₁₋₆, such as C₁₋₄) alkyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkyl, (e.g., C₁₋₆, such as C₁₋₄) alkenyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkenyl, —OH, (e.g., C₁₋₆, such as C₁₋₄) alkoxy, (e.g., C₁₋₆, such as C₁₋₄) haloalkoxy, —O-alkylene-C(O)OH, nitro, —NH₂, (e.g., C₁₋₆, such as C₁₋₄) alkylamino, (e.g., C₁₋₆, such as C₁₋₄) dialkylamino, and (e.g., C₁₋₆, such as C₁₋₄) haloalkylamino.

Embodiment 29. The method of embodiment 25 or 26, wherein the compound of Formula (I) has a structure of Formula (I_(B2)):

wherein:

R^(x6) and R^(x7) are each independently selected from halogen, (e.g., C₁₋₆, such as C₁₋₄) alkyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkyl, (e.g., C₁₋₆, such as C₁₋₄) alkenyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkenyl, —OH, (e.g., C₁₋₆, such as C₁₋₄) alkoxy, (e.g., C₁₋₆, such as C₁₋₄) haloalkoxy, —O-alkylene-C(O)OH, nitro, —NH₂, (e.g., C₁₋₆, such as C₁₋₄) alkylamino, (e.g., C₁₋₆, such as C₁₋₄) dialkylamino, and (e.g., C₁₋₆, such as C₁₋₄) haloalkylamino; or,

alternatively, R^(x6) and R^(x7) together with the atoms to which they are attached to form cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more substituents independently selected from halogen, (e.g., C₁₋₆, such as C₁₋₄) alkyl, and (e.g., C₁₋₆, such as C₁₋₄) haloalkyl.

Embodiment 30. The method of embodiment 25 or 26, wherein the compound of Formula (I) has a structure of Formula (I_(C1)) or (I_(C2)):

wherein:

R^(x8) and R^(x9) are each independently selected from halogen, (e.g., C₁₋₆, such as C₁₋₄) alkyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkyl, (e.g., C₁₋₆, such as C₁₋₄) alkenyl, (e.g., C₁₋₆, such as C₁₋₄) haloalkenyl, —OH, (e.g., C₁₋₆, such as C₁₋₄) alkoxy, (e.g., C₁₋₆, such as C₁₋₄) haloalkoxy, —O-alkylene-C(O)OH, nitro, —NH₂, (e.g., C₁₋₆, such as C₁₋₄) alkylamino, (e.g., C₁₋₆, such as C₁₋₄) dialkylamino, and (e.g., C₁₋₆, such as C₁₋₄) haloalkylamino.

Embodiment 31. The method of embodiment 21, wherein the compound of Formula (I) or the salt thereof is selected from:

and a salt of any one thereof. Embodiment 32. A method for preventing or treating hair loss or hair thinning (whether or not a diagnosis of hair loss or hair thinning has been made), the method comprising administering to a subject in need thereof a composition comprising a compound having a structure of Formula (II):

or a salt thereof, wherein:

-   -   R^(y) is each independently alkyl or haloalkyl;     -   m is 0, 1, or 2;     -   L¹ is selected from bond, —O—, —S—, —N(R^(a1))—, —C(O)—,         —C(O)-alkylene-, —C(O)-alkylene-O—, -alkylene-C(O)—,         -alkylene-C(O)—O—, —C(O)O—, —OC(O)—, —C(O)N(R^(a2))—,         —N(R^(a3))C(O)—, —N(R^(a4))C(O)N(R^(a5))—, —N(R^(a6))C(O)O—,         —OC(O)N(R^(a7))—, —S(O)₂—, —OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—,         —S(O)₂O—, —N(R^(a8))S(O)₂—, —S(O)₂N(R^(a9))—, —N(R^(a10))S(O)—,         —S(O)N(R^(a11))—, —N(R^(a12))S(O)₂N(R^(a13))—, and         N(R^(a14))S(O)N(R^(a15))—; and     -   R¹ is selected from H, alkyl, haloalkyl, alkoxy, haloalkoxy,         alkenyl, haloalkenyl, cycloalkyl, alkylcycloalkyl,         halocycloalkyl, aryl (e.g., phenyl), alkylaryl, heteroaryl,         —O-aryl, —O— alkylaryl, and —O-heteroaryl.         Embodiment 33. The method of embodiment 32, wherein the compound         of Formula (II) has a structure of Formula (II_(A)):

Embodiment 34. The method of embodiment 32 or 33, wherein R^(y) is C₁-C₆ (e.g., C₁-C₄) alkyl (e.g., methyl). Embodiment 35. The method of any one of embodiments 32 to 34, wherein m is 1. Embodiment 36. The method of any one of embodiments 32 to 35, wherein L¹ is selected from —C(O)—, —C(O)-alkylene-O—, and —S(O)₂—. Embodiment 37. The method of any one of embodiments 32 to 37, wherein R¹ is selected from alkyl, cycloalkyl, aryl, alkylaryl, —O-aryl, and —O-alkylaryl. Embodiment 38. The method of embodiment 32, wherein the compound of Formula (II) or the salt thereof is selected from:

and a salt of any one thereof. Embodiment 39. A method for preventing or treating hair loss or hair thinning (whether or not a diagnosis of hair loss or hair thinning has been made), the method comprising administering to a subject in need thereof a composition comprising a compound having a structure of Formula (III):

or a salt thereof, wherein:

-   -   A is aryl or heteroaryl;     -   p is 0, 1, or 2;     -   R^(y) is each independently alkyl or haloalkyl;     -   q is 0, 1, or 2;     -   R^(z) is each independently alkyl or haloalkyl; and     -   R¹ and R² are each independently selected from H, optionally         substituted aryl, —NH—C(O)—NH-cycloalkyl (e.g., adamantyl),         —C(O)—NH-cycloalkyl, and —NH—C(O)-cycloalkyl; or,     -   alternatively, R¹ and R² join together with the nitrogen atom to         which they are attached to form N-heterocyclyl (e.g.,         piperazinyl) or —N═R^(c), wherein R^(c) is an optionally         substituted aryl or optionally substituted heteroaryl.         Embodiment 40. The method of embodiment 39, wherein R¹ and R²         join together with the nitrogen atom to which they are attached         to form

wherein R^(x) is selected from alkyl, haloalkyl, -alkylene-OH, -alkylene-O-alkyl, -alkylene-aryl, and -alkylene-arylene-alkyl. Embodiment 41. The method of embodiment 40, wherein R¹ and R² join together with the nitrogen atom to which they are attached to form

Embodiment 42. The method of embodiment 39, wherein R¹ and R² join together with the nitrogen atom to which they are attached to form an optionally substituted piperazinyl. Embodiment 43. The method of any one of embodiments 39 to 42, A is pyridinyl

Embodiment 44. The method of embodiment 39, wherein the compound of Formula (III) or the salt thereof is selected from:

and a salt of any one thereof. Embodiment 45. A method for preventing or treating hair loss or hair thinning (whether or not a diagnosis of hair loss or hair thinning has been made), the method comprising administering to a subject in need thereof a composition comprising a compound having a structure of Formula (IV):

or a salt thereof, wherein:

-   -   A is heteroaryl;     -   q is 0, 1, 2, or 3; and     -   R^(x) is selected from alkyl, haloalkyl, alkoxyl, haloalkoxyl,         —SH, alkylthio, aryl, and alkoxylaryl.         Embodiment 46. The method of embodiment 45, wherein the compound         of Formula (IV) or the salt thereof is selected from:

and a salt of any one thereof. Embodiment 47. A method for preventing or treating hair loss or hair thinning (whether or not a diagnosis of hair loss or hair thinning has been made), the method comprising administering to a subject in need thereof a composition comprising a compound having a structure of Formula (V):

or a salt thereof, wherein:

-   -   R¹ is H or optionally substituted aryl;     -   R^(m) and R^(n) join together with the nitrogen atom to which         they are attached to form N-heterocyclyl, wherein the         N-heterocyclyl is optionally substituted with one or more         substituents selected from alkyl, —S(O)H, —S(O)₂H, —S(O)-alkyl,         and —S(O)₂-alkyl;     -   Q¹ is NR^(a1), CR^(b1)R^(b2) or S     -   Q³ is N or CR^(b3); and     -   Q² is NR^(a2) or CR^(b4)R^(b5); wherein:     -   R^(a1), R^(a2), R^(b1), R^(b2), R^(b3), R^(b4), and R^(b5) are         each independently selected from H, optionally substituted aryl,         optionally substituted alkylaryl, and optionally substituted         arylalkyl.         Embodiment 48. The method of embodiment 47, wherein Q¹ is         CR^(b1)R^(b2) or S.         Embodiment 49. The method of embodiment 47 or 48, wherein Q³ is         CR^(b3).         Embodiment 50. The method of embodiment 47, wherein the compound         of Formula (V) or the salt thereof is selected from:

and a salt of any one thereof. Embodiment 51. A method for preventing or treating hair loss or hair thinning (whether or not a diagnosis of hair loss or hair thinning has been made), the method comprising administering to a subject in need thereof a composition comprising a compound having a structure of Formula (VI):

or a salt thereof, wherein:

-   -   L⁰ is selected from —C(O)—, —O—, —S—, —C(O)O—, —OC(O)—, —S(O)—,         —S(O)₂—, —NH—, and

wherein L¹ is selected from —C(O)—, —O—, —S—, —C(O)O—, —OC(O)—, —S(O)—, —S(O)₂—, and —NH—;

-   -   p, q, and m are each independently 0, 1, or 2;     -   R^(x), R^(y), and R^(z) are each independently selected from         alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, —OH,         —C(O)OH, or -alkylene-C(O)OH;     -   A is aryl or heteroaryl;     -   L² is alkylene, —C(O)—, —O—, —S—, —C(O)O—, —OC(O)—, —S(O)—,         —S(O)₂—, —N(H)S(O)₂—, —S(O)₂N(H)—, -alkylene-N(H)S(O)₂—,         —S(O)₂N(H)-alkylene-, —NH—, —N═, and —CH═N—N═; and     -   B is an optionally substituted aryl or optionally substituted         heteroaryl.         Embodiment 52. The method of embodiment 51, wherein L⁰ is

Embodiment 53. The method of embodiment 51 or 52, wherein A is phenyl or piperazinyl. Embodiment 54. The method of any one of embodiments 51 to 53, wherein B is selected from

Embodiment 55. The method of any one of embodiments 51 to 54, wherein L² is selected from alkylene, —S(O)₂N(H)-alkylene-, and —CH═N—N═. Embodiment 56. The method of any one of embodiments 51 to 55, wherein p is 0. Embodiment 57. The method of any one of embodiments 51 to 55, wherein p is 1. Embodiment 58. The method of any one of embodiments 51 to 55, wherein p is 2. Embodiment 59. The method of any one of embodiments 51 to 58, wherein q is 0. Embodiment 60. The method of any one of embodiments 51 to 59, wherein m is 0. Embodiment 61. The method of any one of embodiments 51 to 59, wherein m is 2. Embodiment 62. The method of any one of embodiments 51 to 61, wherein R^(x) is each independently cyano, alkyl, alkoxy, and nitro. Embodiment 63. The method of any one of embodiments 51 to 62, wherein R^(z) is each independently —OH, —C(O)OH, or -alkylene-C(O)OH. Embodiment 64. The method of embodiment 51, wherein the compound of Formula (VI) or the salt thereof is selected from:

and a salt of any one thereof. Embodiment 65. A method for preventing or treating hair loss or hair thinning (whether or not a diagnosis of hair loss or hair thinning has been made), the method comprising administering to a subject in need thereof a composition comprising a compound selected from:

and a salt of any one thereof. Embodiment 66. The method of any one of embodiments 1 to 65, wherein the composition is a pharmaceutical composition. Embodiment 67. The method of embodiment 66, further comprising at least one additive selected from the group consisting of pharmaceutically acceptable carriers, excipients, adjuvants, and diluents. Embodiment 68. The method of any one of embodiments 1 to 65, wherein the composition is a cosmetic composition

Embodiment 69. The method of embodiment 68, further comprising at least one additive selected from the group consisting of cosmetically acceptable carriers, excipients, adjuvants, and diluents.

Embodiment 70. The method of any one of embodiments 1 to 69, wherein the cosmetic composition is formulated as toner, emulsion, cream, gel, shampoo, soap, serum, spray, or oil. Embodiment 71 The method of any one of embodiments 1 to 70, wherein the hair loss is selected from androgenic alopecia, alopecia areata, androgenetic alopecia, gynecologic alopecia, postpartum alopecia, seborrheic alopecia, non-rigid alopecia, senile alopecia, chemotherapy-induced alopecia, radiation-induced alopecia, male-pattern baldness, female-pattern baldness, cicatricial alopecia, alopecia areata telogen effluvium, traction alopecia, and anagen effluvium. Embodiment 72. The method of any one of the preceding embodiments, wherein the method promotes hair strength, hair growth, hair restoration or hair thickening of said subject. Embodiment 73. The method of any one of the preceding embodiments, wherein the subject has not been diagnosed. Embodiment 74. The method of any one of the preceding embodiments, wherein the method increases hair density or hair growth rate of said subject. Embodiment 75. The method of any one of the preceding embodiments, wherein the hair is scalp hair, eyelash hair, eyebrow hair, or facial hair.

EXAMPLES

The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention in any way.

Example 1: Assay of Human Follicle Dermal Papilla Cells (hFDPC) Proliferation

The ability of a compound or salt of the present disclosure to increase proliferation of human hair follicle dermal papilla cells (hFDPC) was tested using a cell viability assay, such as the Promega CellTiter-Glo® Luminescent Cell Viability Assay, MTT cell proliferation assay (ATCC® 30-1010K) or cell counting. Table 11 shows the results. In Table 8, A represents less than 20% of increased proliferation of hFDPCs, B represents 20-40%, and C represents larger than 40% of increased proliferation of hFDPCs. For this assay, hFDPCs were cultured on tissue culture-treated plastic and supplemented with 6-bromoindirubin-39-Oxime (BIO), recombinant bone morphogenetic protein-2 (BMP-2), and basic fibroblast growth factor (FGFβ), whose combination was previously found to preserve in situ dermal papilla gene signatures. An exemplary result using compound VII-3 is shown in FIG. 1 .

TABLE 11 Evaluation of small molecules based on hFDPC proliferation ID Percent Increase Proliferation # Chemical Structure of hFDPCs (%) I-1 

A I-2 

B I-3 

A I-4 

A I-5 

B I-6 

A I-7 

A I-8 

B I-9 

B I-10

A I-11

A I-12

B I-13

A I-14

A I-15

B I-16

A I-17

C I-18

B II-1

A II-2

B II-3

B II-4

B II-5

B II-6

B III-1

A III-2

A III-3

B III-4

B III-5

A IV-1

B IV-2

A IV-3

B IV-4

A V-1

A V-2

A V-3

B V-4

A VI-1

A VI-2

B VI-3

B VI-4

A VI-5

A VI-6

A VII-1 

C VII-2 

A VII-3 

B VII-4 

A VII-5 

A VII-6 

A VII-7 

B VII-8 

A VII-9 

B VII-10

B VII-11

A VII-12

A VII-13

A VII-14

A VII-15

A VII-16

A VII-17

A VII-18

A VII-19

A VII-20

A VII-21

A VII-22

A VII-23

B VII-24

A VII-25

B VII-26

A A represents less than 20% of increased proliferation of hFDPCs, B represents 20-40%, and C represents larger than 40% of increased proliferation of hFDPCs.

Example 2: Assay on Keratinocytes

Human adult epidermal keratinocytes were cultured on poly-L-lysine treated plates and the ability of a compound or salt of the present disclosure to impact proliferation was measured using a cell viability assay, such as Promega CellTiter-Glo® Luminescent Cell Viability Assay, MTT cell proliferation assay (ATCC® 30-1010K) or cell counting after 48 hr. The compound or salt was added at different concentrations spanning at least a 2-log range.

Example 3: Assay on Fibroblasts

The ability of a compound or salt of the present disclosure to impact proliferation of human adult dermal fibroblasts was tested using a cell viability assay, such as Promega CellTiter-Glo® Luminescent Cell Viability Assay, MTT cell proliferation assay (ATCC® 30-1010K) or cell counting after 48 hr. The compound or salt was added at different concentrations spanning at least a 2-log range.

Example 4: Assay on Endothelial Cells

The ability of a compound or salt of the present disclosure to impact proliferation of human adult dermal microvascular endothelial cells was tested using a cell viability assay, such as Promega CellTiter-Glo® Luminescent Cell Viability Assay, MTT cell proliferation assay (ATCC® 30-1010K) or cell counting after 48 hr. The compound or salt was added at different concentrations spanning at least a 2-log range.

Example 5: In Silico Safety/Toxicology Studies

The in silico safety/toxicology profiles of compounds were determined by screening chemical structures against a series of computational models. These include the Pred-hERG 4.2 cardiotoxicity model and the NeuroDeRisk IL Profiler neurotoxicity model, as well as reproductive and developmental toxicity, carcinogenicity (genotoxic and non-genotoxic), skin sensitization, DNA mutation, and chromosomal aberration models from QSAR Toolbox.

Example 6: Safety/Toxicology Studies

The safety/toxicology profiles of a compound or salt of the present disclosure was evaluated via a series of in vitro genotoxicity assays, including the SOS-chromotest to determine bacterial genotoxicity, and the TK.6 micronucleus assay to determine chromosomal damage and forward mutations. Standard reactive oxygen species (ROS) and caspase 3/7 assay were conducted to determine general cellular toxicity. Moreover, a series of sensitization tests were conducted to predict any potential skin sensitivity. These include the direct peptide reactivity assay to evaluate haptenization, the KeratinoSens reporter assay to determine potential sensitivity via the activation of a cytoprotective pathway, and an immunological assay using human immature monocyte-derived dendritic cells to evaluate any potential immunogenicity.

Future studies will include mechanism-oriented studies, including metabolism and transport studies focusing on the ability of a compound or salt of the present disclosure to induce or inhibit cytochrome P450, passive/active transport using the caco-2 cell line and compound efflux using the MDR-MDCK cell line, all well-established assays. Additional safety and toxicity studies include functional cardiotoxicity and neurotoxicity in human iPSC-derived cardiomyocytes and neurons, respectively. Finally, a repeated insult patch test will be performed using a compound or salt of the present disclosure on 200 human subjects to predict induced allergic contact dermatitis and associated responses.

Example 7: Efficacy Studies

The functional profile of a compound or salt of the present disclosure continues to be investigated in a number of 3D cellular and ex vivo models, and ultimately clinical trials. Additionally, transcriptomic and proteomic analyses will be conducted on relevant genes and proteins with well-established functional roles such as VEGF or beta-catenin on cells exposed to a compound or salt of the present disclosure. The “two-cell assemblage” (TCA) 3D co-culture model, which involves coating human outer root sheath cells (hORS) on top of a dense spheroid of human follicle papilla cells, will continue to be used. The hFDPCs support the polar outgrowth of the hORS, resembling a hair-like bulb-in-a-dish. Additionally, a compound or salt of the present disclosure will be treated on excised live human skin (containing hair) grafts from cosmetic surgeries and evaluate the targeted activation of follicle papilla cells in histology studies. Finally, a clinical efficacy trial will be performed with 30 human subjects with hair loss or hair thinning to determine effectiveness of a compound or salt of the present disclosure to promote hair growth. Additional trials with more subjects and spanning wider age groups and demographics may follow.

Example 8: Mechanistic Analysis

Using the transcriptomics data, a series of mechanistic computational analyses will be performed to identify possible mechanisms of action. These may include DE analyses followed by GO term and pathway enrichment to characterize the biological imprint of the exemplary chemicals. In addition, pseudo-time and cell-cycle analyses will be performed to probe the developmental effects of these chemicals on target cells. The extracted insight in further investigations and models will be validated.

Example 9: Exemplary Compound does not Disrupt Intestinal Cell Barrier Integrity in a Caco-2 Monolayer System

This example shows the measurement of the rate of flux of a compound across polarized Caco-2 cell monolayers and the data generated can be used to predict in vivo absorption of compounds. FIG. 2A is a schematic representation of model system. Caco-2 cells were cultured on transwells and cultured until a monolayer formed, mimicking the intestinal cell barrier. The cultures were treated with an exemplary compound (VII-3) or vehicle control (0.1% v/v DMSO) on the apical side for 24 hr and cultured in media containing a fluorescent dye (Lucifer yellow, labeled “F”). FIG. 2B shows apparent permeability of a Caco-2 monolayer dosed with DMSO and a representative compound. There was no observed difference in apparent permeability. Data represents mean±s.d. and representative of at least 2 experimental replicates.

Example 10: Exemplary Compounds Exhibit No Genotoxic Transformation Potential

TK.6 lymphoblasts are a well-studied cell line commonly used for gene mutation analyses. They are heterozygous for the thymidine kinase gene (TK) and enable the detection of forward mutations and chromosomal damage, which manifests as micronuclei and are detectable via flow cytometry.

TK.6 cells were dosed with the exemplary compounds or a vehicle control (0.1% v/v DMSO) and cultured with or without S9 metabolic activation for 24 hr. FIG. 3A shows representative plots of TK.6 cells treated with an exemplary compound (VII-3), with or without S9 metabolic activation. Methyl methanesulfonate, a known genotoxic, alkylating agent was used as a positive control for micronuclei detection. By comparison of the plots, the representative compound did not exhibit genotoxic effect.

The micronucleus assay was also performed to determine if the compounds are genotoxic by evaluating the presence of micronuclei. FIG. 3B shows quantification of TK.6 micronuclei assay following treatment with various exemplary compounds across a concentration range without S9 metabolic activation. FIG. 3C shows quantification of TK.6 micronuclei assay following treatment with various exemplary compounds across a concentration range with S9 metabolic activation. In combination, FIGS. 3B and 3C show that the exemplary compounds VII-3, VII-1, VII-14, and II-4 do not promote any micronuclei formation, thus demonstrating no genotoxic transformation potential, in the absence or presence of S9 metabolic activation. I-17 elicited genotoxicity at >3.125 ug/mL.

FIG. 3D shows normalized β-galactosidase activity (as quantified via absorbance) from the SOS chromotest using a known genotoxin (4-NQ; 4-nitroquinoline-1-oxide) and representative compounds at varying concentrations. The SOS chromotest is a well-established bacteria-based test for genotoxicity. Similar to the results of the micronucleus assay, compounds VII-3, VII-1, and II-4 did not exhibit any genotoxic effects.

Normalized reactive oxygen species (ROS) activity in follicle dermal papilla cells were analyzed after treatment with 5 μg/mL exemplary compounds relative to vehicle control (0.1% v/v DMSO) after 24 hr. The increase in ROS levels is harmful on cell mhemeostasis, structures, and functions and results in oxidative stress. As shown in FIG. 3E, the ROS level of I-18 was higher than other compounds.

HepG2 cells are an immortalized liver cell line commonly used to study apoptosis induced by small molecules. Normalized caspase 3/7 activity in HepG2 was measured as shown in FIG. 3F. Cells were treated with either the exemplary compounds or vehicle control containing correspondingly % v/v-matched amounts of DMSO spanning a >2-log concentration range. Data represents mean±s.d. and representative of at least 2 experimental replicates. Aside from compound I-17, which resulted in significant caspase-3/7 activation at the highest concentration, compounds VII-3, VII-1, VII-14, and II-4 did not exhibit any caspase activation across a 2-log concentration range.

Example 11: Exemplary Compounds do not Exhibit any Skin Sensitizing Potential or Immunogenicity

The Nrf2-ARE pathway is a master regulator of cytoprotective responses to oxidative stress, and is an early indicator of skin sensitization. Nrf2 (nuclear factor erythroid 2-related factor) is a transcription factor that binds to antioxidant responsive elements (ARE). By fusing ARE to the light-producing luciferase gene, a KeratinoSens Nrf2-ARE reporter assay was performed whereby luciferase signal is directly correlated to Nrf2-ARE pathway activation.

Normalized ARE-luciferase activity was measured using a known sensitizing compound (cinnamic aldehyde) and exemplary compounds. Compound VII-1 exhibited sensitizing potential (FIG. 4A).

To evaluate skin sensitizing potential or immunogenicity, in vitro dendritic cell sensitization test was also performed. Dendritic cell activation is widely-associated with downstream immunogenicity. CD14+ cells from human donor peripheral mononuclear cells were harvested and differentiated them into immature monocyte-derived DCs using granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4), then treated with the exemplary compounds. Killed E. Coli and TNF-α were used as positive controls. FIG. 4B shows representative plots showing change in HLA-DR expression. FIGS. 4C, 4D, and 4E show expression of CD80, PDL-1, and CD141, respectively, as quantified via mean fluorescence intensity (MFI) following dosing with various exemplary compounds. Data represents mean±s.d. and representative of at least 2 experimental replicates. exemplary compounds did not exhibit any skin sensitizing potential or immunogenicity

Example 12: Exemplary Compounds do not Elicit Caspase-3 Activation in Skin Tissues Ex Vivo

Leftover hair-containing skin tissue from cosmetic surgeries was biopsy-punched and prepared as ready-to-use skin models (Genoskin). The samples were preserved and cultured for ex vivo testing with vehicle control (distilled water) or exemplary compounds for 24 hrs, then processed for two-photon microscopy.

FIG. 5A are representative images of ex vivo epithelial samples of epidermal tissue surrounding hair follicles 24 hr following treatment. Samples were stained for Caspase-3 and with DAPI. Inset shows representative image of ex vivo skin model.

Average corrected fluorescence of cells stained for caspase-3 were measured for samples treated with various representative compounds. Images and data are representative of tissues derived from n=2 donors. As shown in FIG. 5B, exemplary compounds did not elicit Caspase-3 activation in skin tissues ex vivo.

Example 13: Clinical Repeat Insult Patch Test

The clinical test was performed by Eurofins|CRL, Inc. The test followed established, standardized procedures for clinical testing designed to ensure the well-being of clinical study subjects and the generation of reliable study data. A total of 239 male and female subjects, ranging in age from 18 to 70 year were selected for study participation. The objective of the study was to determine the potential of the test material containing 0.02% v/v of the exemplary compound in eliciting dermal irritation and/or induce sensitization following repeated patch applications.

TABLE 12 Clinical repeat insult patch test Subjects Completed Sex Patch type Adverse reactions 218/239 58 M Occlusive 0/218 (0%) (20 subjects lost during and 1 subject exhibited erythema, papules, follow-up, 1 subject excluded 160 F pustules and post-inflammatory due to unrelated event) hyperpigmentation consistent with acne due to an unrelated event and was excluded from the study

Example 14: Clinical Consumer Perception Study

The clinical test was performed by Eurofins|CRL, Inc. The test followed established, standardized procedures for clinical testing designed to ensure the well-being of clinical study subjects and the generation of reliable study data. Subjects were female and ranged in age from 27-65 years. Subjects used a simple, water-based formula containing a exemplary compound, VII-3 (at 0.02% v/v) every 2 days in the morning or night on dry or towel-dried hair. Approximately 2 mL was applied directly to the hairline. No randomization was required for the study and subjects were blinded to the name of the test material.

TABLE 13 Clinical consumer perception study using compound VII-3 Questions Subjects who saw Subjects with Subjects who Study improvements in tight hairstyles saw increased Subjects Adverse their hair's who noticed hair growth Completed effects Analysis Blinding appearance less shedding and thickness 32/35 0/32 (0%) 6 weeks Subjects were 31/32 (97%) 28/32 (87%) 26/32 (82%) (3 subjects (digital blinded to the lost during photography) name of the follow-up) test material

Example 15: Subjects' Hair in Clinical Consumer Perception Study

Photographs of subjects' hair were taken 6 weeks after the treatment with the representative compounds (FIG. 6 ). Subjects were female and ranged in age from 27-65 years. Subjects used a simple, water-based formula containing an exemplary compound VII-3 (at 0.02% v/v) every 2 days in the morning or night on dry or towel-dried hair. Approximately 2 mL was applied directly to the hairline. No randomization was required for the study and subjects were blinded to the name of the test material. FIG. 6 . highlights specific regions of the included participants' scalps, juxtaposing pictures taken before and after the study. Based on clinical surveys, 97% of women reported an improvement in their hair's appearance while 82% reported increased hair growth and thickness.

Example 16: Exemplary Compound is Functionally Stable Across Physiologically-Relevant pH and Temperature Ranges

An exemplary compound (VII-3) was prepared in various solvents (DMSO; dimethyl sulfoxide, DMI; dimethyl isosorbide, or a 1:1 mixture of dimethyl isosorbide and ethanol), the diluted in pH-adjusted water and left at varying temperatures for 7 days. Human follicle papilla cells were dosed at 5 ug/mL with the exemplary compound and further supplemented with 6-bromoindirubin-39-Oxime (BIO), recombinant bone morphogenetic protein-2 (BMP-2), and basic fibroblast growth factor (FGFβ), whose combination was previously found to preserve in vivo dermal papilla gene signatures. Normalized proliferation follicle papilla cell proliferation was analyzed after 48 hr following the treatment with the exemplary compound pre-treated across a range of pH conditions (FIG. 7A) and temperature conditions (FIG. 7B). Data represents mean±s.d. and representative of n=2 donors. The resulting data showed that the exemplary compound is functionally stable across physiologically-relevant pH and temperature ranges.

Example 17: An Exemplary Synthesis Method of Compound VII-3

Synthesis of an exemplary compound, VII-3 was carried out following Scheme 1 given below;

The synthesis could be performed in two different ways. As the first method, to a water solution of EtOH (100 ml of water and 100 ml of EtOH), NaOH was added during 20 min at room temperature. 3-(furan-2-yl)-1H-1,2,4-triazole-5(4H)-thione (20 g, 0.1 mol) was added by portions at room temperature with stirring. The mixture was stirred at room temperature for 1 h. Mel was added by drop at room temperature for 25 min and stirred the mixture for 12 h. The solution was evaporated to half the volume under reduced pressure (50° C., 20 mm), precipitate was filtered off, washed with water (3×100 ml) and dried. Final yield of the target compound was 68%.

The compound was also synthesized by the second method as follows. 3-(furan-2-yl)-5-(methylthio)-4H-1,2,4-triazole (18 g) was mixed with dry THF (125 ml) and NEt3 was added by drop at 5° C. To a water solution of EtOH (100 ml of water and 100 ml of EtOH) NaOH was added during 20 min at room temperature. The mixture was cooled to 5° C. and MeSO₂Cl was added by drop, stirred for 1 h at 10° C. and 12 h at room temperature. 500 ml of water was added and stirred for 1 h. The precipitate was filtered, washed with water (3×80 ml), and dried. The product was purified by column chromatography (eluent MTBE/CH₂Cl₂ 50/50). Solvent was evaporated. Final yield of the target compound was 72%.

While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby. 

What is claimed is:
 1. A method for preventing or treating hair loss or hair thinning (whether or not a diagnosis of hair loss or hair thinning has been made), the method comprising administering to a subject in need thereof a composition comprising a compound having a structure of Formula (VII_(B)):

or a salt thereof, wherein: B is aryl or heteroaryl, wherein the heteroaryl is selected from pyridine, pyrimidine, oxazole, furan, pyran, thiophene, isoxazole, benzimidazole, benzthiazole, and imidazopyridine; R¹ is selected from hydrogen, C₁₋₆ alkyl or C₁₋₆ haloalkyl, —S-alkyl, —S-haloalkyl, —S(O)(O)R^(a); wherein R^(a) is selected from the group consisting of hydrogen, C₁₋₆ alkyl, or C₁₋₆ haloalkyl; R² is selected from —OH, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —SR^(b), —NH₂, alkylamino, and imino, wherein R² is selected from the group consisting of hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and

 and R³ and R⁴ is independently selected from the group consisting of hydrogen, C₁₋₆ alkyl or C₁₋₆ haloalkyl.
 2. The method of claim 1, wherein B is heteroaryl.
 3. The method of claim 2, wherein the heteroaryl is furan.
 4. The method of claim 1, wherein R¹ is hydrogen or S(O)(O)R^(a).
 5. The method of claim 4, wherein R^(a) is methyl or ethyl.
 6. The method of claim 1, wherein R² is imino or —SR^(b).
 7. The method of claim 6, wherein R^(b) is methyl or


8. The method of claim 1, wherein R³ is hydrogen or ethyl.
 9. The method of claim 1, wherein R⁴ is hydrogen.
 10. The method of claim 1, wherein the compound of Formula (VII_(B)) or the salt thereof is selected from:


11. A method for preventing or treating hair loss or hair thinning (whether or not a diagnosis of hair loss or hair thinning has been made), the method comprising administering to a subject in need thereof a composition comprising a compound having a structure of Formula (VII_(A)):

or a salt thereof, wherein: A is aryl or heteroaryl, wherein the heteroaryl is selected from pyridine, pyrimidine, oxazole, furan, pyran, thiophene, isoxazole, benzimidazole, benzthiazole, and imidazopyridine; R¹ is C₁₋₆ alkyl or C₁₋₆ haloalkyl; and R² is —C(O)OH, —C(O)O-alkyl, or —C(O)O-haloalkyl.
 12. The method of claim 11, wherein A is aryl.
 13. The method of claim 12, wherein the aryl is phenyl.
 14. The method of claim 11, wherein R¹ is C₁₋₆ alkyl.
 15. The method of claim 12, wherein R² is —C(O)O-alkyl.
 16. The method of claim 8, wherein the compound of Formula (VII_(A)) is

or a salt thereof.
 17. A method for preventing or treating hair loss or hair thinning (whether or not a diagnosis of hair loss or hair thinning has been made), the method comprising administering to a subject in need thereof a composition comprising a compound having a structure of Formula (VIII):

or a salt thereof, wherein: m is 0, 1, or 2; and R^(x) is each independently C₁₋₆ alkyl, C₅₋₈ aryl, C₁₋₆ haloalkyl, alkylaryl, or haloalkylaryl.
 18. The method of claim 17, wherein m is
 2. 19. The method of claim 17, wherein R^(x) is each independently methyl or phenyl.
 20. The method of claim 17, wherein the compound of Formula (VIII) is

or a salt thereof. 